TW201831465A - Metalloenzyme inhibitor compounds, methods of inhibiting metalloenzyme activity, methods for using the metalloenzyme inhibitor compounds and pharmaceutical compositions - Google Patents

Abstract

Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

Description

   Metalloenzyme inhibitor compound, method for inhibiting metalloenzyme activity, method for using metalloenzyme inhibitor compound, and pharmaceutical composition   

Cross-references to related applications

This application claims priority from US Provisional Patent Application No. 62 / 440,181 filed on December 29, 2016 based on 35 U.S.C. § 119 (e). The entire contents of this provisional patent application are incorporated herein by reference.

Aldosterone is a steroid hormone secreted from the adrenal gland that binds and activates the mineralocorticoid receptor (MR). In the primary cells of the distal tubules and collecting tubules of the kidney, MR activation leads to sodium and water retention and excretion of potassium, which causes the plasma volume to expand and cause increased blood pressure (BP). The excess aldosterone measured in the circulation is called primary aldosteronism (PA) and occurs when aldosterone production is imbalanced by the renin-angiotensin-aldosterone system (RAAS). . PA was originally identified in patients with adrenal adenoma, with recent evidence suggesting an increased prevalence associated with obesity. PA is a common cause of secondary hypertension. The prevalence of PA in patients with resistant hypertension (RHTN) ranges from 14-21%. It is a disease defined as BP remaining above target. Condition, regardless of the concurrent use of three antihypertensive agents of different classes including diuretics. Recent studies have demonstrated an association between excess aldosterone, RHTN, and obstructive sleep apnea (OSA), which is exacerbated by aldosterone-mediated retention of body fluids.

Local overproduction of aldosterone has been noted in several severe disease states, even when no significant plasma rise has been observed. In patients with chronic congestive heart failure (CHF), the level of aldosterone in the heart tissue of the failing heart is higher than that of peripheral plasma. In animal models of kidney disease, local production of aldosterone in the renal cortex is assumed to contribute to the disease process. In both of these states, locally elevated aldosterone levels contribute to deleterious effects via MR-dependent and MR-independent mechanisms, including the generation of reactive oxygen species and the stimulating endothelium that causes inflammation and cell growth and proliferation Dysfunction in which upregulated collagen deposition leads to fibrosis.

Antagonists of MR including spironolactone and eplerenone have been widely used to block the effect of aldosterone binding to MR. The combination of these agents with angiotensin-converting enzyme (ACE) inhibitors and diuretics (RALES & EPHESUS trial) has demonstrated significant morbidity and mortality in patients with heart failure or myocardial infarction cut back. Side effects including hyperkalemia are seen with the use of two agents and non-selective spironolactone, which also triggers gynecomastia through the non-selective regulation of progesterone and androgen receptors ). In addition, the increase in renin and aldosterone results from MR antagonism and thus exacerbates the MR-independent (non-genomic) effect of aldosterone.

In contrast to MR antagonists, the inhibition of CYP11B2 (aldosterone synthase), a key enzyme in aldosterone biosynthesis, should provide the beneficial effects of MR antagonism without the harmful accumulation of activated aldosterone that causes MR independent inflammation and fibrotic state. CYP11B2 is a mitochondrial cytochrome P450 enzyme that converts 11-deoxycorticosterone to aldosterone. Selective inhibition of CYP11B2 represents a promising treatment for aldosterone-related diseases.

The highly homologous metalloenzyme CYP11B1 (11-β-steroid-hydroxylase) catalyzes the formation of primary glucocorticoid cortisol from 11-deoxycortisol. Given the high degree of homology (93%) between CYP11B2 and CYP11B1, the development of selective CYP11B2 inhibitors has been an important challenge. The inhibitor Osilodrostat (LCI-699) was developed as an inhibitor of CYP11B2 for the treatment of hypertension, but was abandoned due to its effective inhibition of CYP11B1. Described herein are selective compounds that block the production of aldosterone via CYP11B2 without inhibiting the production of cortisol via CYP11B1.

Living organisms have generated tightly regulated processes that specifically introduce metals, transport them to intracellular storage sites, and eventually transport these metals to sites of use. One of the most useful functions of metals such as zinc and iron in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the active site of an enzyme and use metals as part of a catalytic process. More than a third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of metal ions in the active site of the enzyme. It should be fully recognized that agents that bind and inactivate metal ions at the active site significantly reduce enzyme activity. This same strategy is used in nature to reduce the activity of certain metalloenzymes during periods where enzyme activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds to zinc ions in the active site of various matrix metalloproteinases and thus prevents enzyme activity. The pharmaceutical industry has used the same strategy to design therapeutics. For example, the azole antifungals fluconazole and voriconazole contain 1- (1,2,4-triazole) groups that bind to the target enzyme lanosterol demethylase Blood plasma iron in the active site, and thus inactivate the enzyme. Another example includes zinc-binding hydroxylate groups, which have been incorporated into most disclosed inhibitors of matrix metalloproteinases and tissue protein deacetylases. Another example is a zinc-binding carboxylic acid group, which has been incorporated into most disclosed angiotensin-converting enzyme inhibitors.

In designing clinically safe and effective metalloenzyme inhibitors, it is desirable to use the appropriate metal-binding group for any particular target and clinical indication. If a weakly-binding metal-binding group is used, the efficiency may be suboptimal. On the other hand, if extremely tightly-binding metal-binding groups are used, the selectivity for the target enzyme relative to the related metalloenzyme can be suboptimal. The lack of optimal selectivity can be the cause of clinical toxicity due to these unwanted inhibitions that deviate from the target metalloenzymes. An example of such clinical toxicity is the undesired inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by currently available azole antifungals such as fluconazole and voriconazole. The inhibition of Xianxin's off-target is mainly through the indiscriminate combination of currently used 1- (1,2,4-triazole) with iron in the active sites of CYP2C9, CYP2C19, and CYP3A4. Another example of this is joint pain, which has been observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to the inhibition of off-target metalloenzymes due to the indiscriminate binding of the hydroxyl group to the zinc in the off-target active site.

Therefore, the search for metal-binding groups that achieve a better balance of potency and selectivity remains an important goal and will achieve treatments that address currently unmet needs in the treatment and prevention of diseases, disorders and their symptoms. Agents and methods are meaningful.

The present invention is directed to compounds (e.g., any of the compounds described herein; any formula described herein), a method of modulating the activity of a metalloenzyme, and a method of treating a disease, disorder, or symptom thereof. These methods may include compounds herein.

It should be understood that the embodiments of the present invention discussed below regarding the selection of preferred variables may be performed alone or in combination with one or more embodiments or the preferred variable selection of the present invention, as if each combination were explicitly listed herein. .

In one aspect, a compound of formula I is provided:

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: A is N or CR ⁵ ; W is N or CR ⁶ ; X is N or CR ⁶ ; Y is N or CR ⁶ ; Z is N or CR ⁶ ; provided that no more than two of W, X, Y, and Z are N; R ¹ Are hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, Heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e COR ^f , S (O) R ^d , S (O) ₂ R ^d , CH ₂ OR ^f , or CR ^e R ^f OH, wherein any R ¹ can be optionally substituted with 1 to 3 independent substituents R ⁷ ; R ² is hydrogen, halogen, cyano, alkyl, or haloalkyl; or R ¹ and R ² together with the atoms attached thereto form an aryl, heterocycloalkyl, or cycloalkyl ring; R ³ is Hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkane Oxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH; R ⁴ is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; R ⁵ is hydrogen , Alkyl, haloalkyl, heteroalkyl, or cycloalkyl; each occurrence of R ⁶ is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, halo Alkyl or carboxy; each occurrence of R ⁷ is independently halogen, alkyl, alkoxy, haloalkyl, carboxy, aryl, aryl substituted with 1 to 3 independent halogens,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h ; each n is independently 1, 2, 3, 4, 5, 6 , 8, 9, or ^{10; R a, R b,} R c, R d, R e, and R ^f each occurrence of the system independently hydrogen, acyl, alkoxy, alkyl, Alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkane Radical, nitrogen protection when attached to a nitrogen atom , Or when the oxygen protecting group attached to an oxygen atom; or R ^a and R ^b together with the atom attached thereto form a heterocycloalkyl ring; or R ^e and R ^f together with the atom attached thereto form a ring together alkyl ring; and ^{R g, R h, R i} , R ^j, and based on each occurrence of is independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, , Heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkyl, or R ^g and ^Rh together with the atoms attached thereto Heterocycloalkyl ring.

In certain embodiments, R ¹ is aryl, heteroaryl, or heterocycloalkyl, wherein any R ¹ may be optionally substituted with 1 to 3 independent substituents R ⁷ .

In certain embodiments, R ¹ is aryl, heteroaryl, or heterocycloalkyl, wherein any R ¹ may be optionally substituted with 1 to 3 independent substituents R ⁷ , and each R ⁷ is independently Is halogen, alkyl, alkoxy, haloalkyl, carboxyl,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h And each R ^g and R ^h are independently hydrogen, alkyl, C (O) C _1-6 alkyl, or R ^g and R ^h together with the atoms attached thereto form a heterocycloalkyl ring.

In certain embodiments, R ¹ is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl , NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , COR ^f , or CR ^e R ^f OH; or R ¹ and R ² are formed together with the atoms attached thereto Aryl ring.

In certain embodiments, R ¹ is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR ^a R ^b , CH ₂ NHSO ₂ R ^d , or CR ^e R ^f OH; or R ¹ and R ² together with the atoms attached thereto form an aryl ring.

In certain embodiments, R ¹ is hydrogen, halogen, alkyl, haloalkyl, CH ₂ NHSO ₂ R ^d , or NR ^a R ^b ; and R ^a , R ^b , and ^Rd are independently hydrogen, Alkyl, or haloalkyl.

In certain embodiments, R ¹ is alkyl or haloalkyl.

In certain embodiments, R ¹ is C _1-6 alkyl or C _1-6 haloalkyl.

In certain embodiments, R ¹ is haloalkyl.

In certain embodiments, R ¹ is C _1-6 haloalkyl.

In certain embodiments, R ¹ is fluoroalkyl. In certain embodiments, R ¹ is C _1-6 fluoroalkyl. In certain embodiments, R ¹ is C _1-3 fluoroalkyl. In certain embodiments, R ¹ is difluoromethyl or trifluoromethyl. In certain embodiments, R ¹ is difluoromethyl. In certain embodiments, R ¹ is trifluoromethyl.

In certain embodiments, R ² is hydrogen or alkyl.

In certain embodiments, R ² is hydrogen or C _1-6 alkyl.

In certain embodiments, R ² is hydrogen or C _1-3 alkyl.

In certain embodiments, R ² is alkyl. In certain embodiments, R ² is C _1-6 alkyl. In certain embodiments, R ² is C _1-3 alkyl. In certain embodiments, R ² is hydrogen.

In certain embodiments, R ¹ is hydrogen and R ² is alkyl. In certain embodiments, R ¹ is hydrogen and R ² is C _1-6 alkyl. In certain embodiments, R ¹ is hydrogen and R ² is C _1-3 alkyl.

In certain embodiments, R ⁴ is alkyl or cycloalkyl.

In certain embodiments, R ⁴ is C _1-4 alkyl or C _3-5 cycloalkyl.

In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is C _3-5 cycloalkyl. In certain embodiments, R ⁴ is cyclopentyl. In certain embodiments, R ⁴ is cyclobutyl. In certain embodiments, R ⁴ is cyclopropyl.

In certain embodiments, each R ⁶ is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxy.

In certain embodiments, each R ⁶ system is independently hydrogen, halogen, or cyano.

In certain embodiments, each R ⁶ is independently hydrogen, chloro, fluoro, or cyano.

In certain embodiments, each R ⁶ is independently hydrogen, fluoro, or cyano.

In certain embodiments, each R ⁶ series is independently hydrogen, or halogen.

In certain embodiments, each R ⁶ system is independently hydrogen, chloro, or fluoro.

In certain embodiments, each R ⁶ system is independently hydrogen or fluoro.

In certain embodiments, each R ⁶ system is independently hydrogen or cyano.

In certain embodiments, each R ⁶ is halogen. In certain embodiments, each R ⁶ is chloro or fluoro. In certain embodiments, each R ⁶ is fluoro. In certain embodiments, each R ⁶ is cyano.

In certain embodiments, A is CR ⁵ and R ⁵ is hydrogen, C _1-4 alkyl, or C _3-5 cycloalkyl.

In certain embodiments, A is N.

In some embodiments, no more than one of W, X, Y, and Z is N.

In certain embodiments, W, X, Y, and Z are each CR ⁶ .

In certain embodiments, Z is N.

In certain embodiments, the compound of formula I is a compound of formula Ia :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , A, X, and Z are as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Ib :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , W, X, Y, and Z are as defined herein.

In certain embodiments, the compound of formula I is a compound of formula Ic :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , and Z are as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Id :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , and Z are as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Ie :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , R ⁶ and Z are as defined herein.

In certain embodiments, a compound of formula I is a compound of formula If :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , And R ⁶ are as defined herein.

In certain embodiments, If a compound of the above formula as their compounds wherein: R ⁴ is alkyl or cycloalkyl; and R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and R ⁶ is halo.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo; and R ¹ is hydrogen , Halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo; and R ¹ is Substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl are required.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and R ⁶ is hydrogen or halo, at least one of which R ⁶ is a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and R ⁶ is halo.

In certain embodiments, a compound of formula I is a compound of formula Ig :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , And R ⁶ are as defined herein.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and R ⁶ is halo.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo; and R ¹ is hydrogen , Halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; R ⁶ is hydrogen or halo, wherein at least one R ⁶ is halo; and R ¹ is Substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl are required.

In another aspect, a compound of formula I is provided:

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein: A is N or CR ⁵ ; W is N or CR ⁶ ; X is N or CR ⁶ ; Y is N or CR ⁶ ; Z is N or CR ⁶ ; provided that no more than two of W, X, Y, and Z are N; R ¹ Are hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, Heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , OR ^f , SR ^f , CO ₂ Re ^e , COR ^f , S (O) R ^d , S (O) ₂ R ^d , CH ₂ OR ^f , or CR ^e R ^f OH, where any R ¹ can be passed through 1 to 3 as needed R ^{7 is} independently substituted; R ² is hydrogen, halogen, cyano, alkyl, or haloalkyl; or R ¹ and R ² together with the atoms attached thereto form an aryl, heterocycloalkyl, or cycloalkyl ring; R ³ is hydrogen, halo, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy Cycloalkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, _{^{heterocycloalkylalkyl, NR a R b, NHSO 2}} R c, CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH; R ⁴ is alkyl, cycloalkyl, haloalkyl, or heteroalkane R ⁵ is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; each occurrence of R ⁶ is independently hydrogen, halogen, cyano, haloalkyl, alkyl, Cycloalkyl, alkoxy, haloalkyl, OR ^f , or carboxyl; each occurrence of R ⁷ is independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, Aryl substituted with 1 to 3 independent halogens,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h ; each n is independently based 1,2,3,4,5,6,7,8,9, or 10; R ^a, at each occurrence ^{R b, R c, R d} , R e, and R ^f independently of the system Ground is hydrogen, fluorenyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R ^a and R ^b together with the atom attached thereto form a heterocycloalkyl ring; or R ^e and R ^f together with the atoms attached thereto form a cycloalkyl ring; and each occurrence of R ^g , R ^h , R ⁱ , and R ^j is independently hydrogen, fluorenyl, alkyl, alkenyl, Alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkyl, or R ^g and R ^h together with the atoms attached thereto form a heterocycloalkyl ring.

In certain embodiments, R ¹ is aryl, heteroaryl, or heterocycloalkyl, wherein any R ¹ may be optionally substituted with 1 to 3 independent substituents R ⁷ .

In certain embodiments, R ¹ is aryl, heteroaryl, or heterocycloalkyl, wherein any R ¹ may be optionally substituted with 1 to 3 independent substituents R ⁷ , and each R ⁷ is independently Is halogen, alkyl, alkoxy, haloalkyl, carboxyl,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h And each R ^g and R ^h are independently hydrogen, alkyl, C (O) C _1-6 alkyl, or R ^g and R ^h together with the atoms attached thereto form a heterocycloalkyl ring.

In certain embodiments, R ¹ is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl , NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , SR ^f , COR ^f , or CR ^e R ^f OH; or R ¹ and R ² together with attached to The atoms together form an aryl or cycloalkyl ring.

In certain embodiments, R ¹ is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , SR ^f , or CR ^e R ^f OH; or R ¹ and R ² together with the atoms attached thereto form an aryl or cycloalkyl ring.

In certain embodiments, R ¹ is hydrogen, halogen, alkyl, haloalkyl, CR ^e R ^f NHSO ₂ R ^d , SR ^f , or NR ^a R ^b ; and R ^a , R ^b , R ^d , R ^e and R ^f are independently hydrogen, alkyl, or haloalkyl.

In certain embodiments, R ¹ is SR ^f . In certain embodiments, R ¹ is SR ^f ; and R ^f is hydrogen, alkyl, or haloalkyl.

In certain embodiments, R ¹ is alkyl or haloalkyl.

In certain embodiments, R ¹ is C _1-6 alkyl or C _1-6 haloalkyl.

In certain embodiments, R ¹ is haloalkyl.

In certain embodiments, R ¹ is C _1-6 haloalkyl.

In certain embodiments, R ¹ is fluoroalkyl. In certain embodiments, R ¹ is C _1-6 fluoroalkyl. In certain embodiments, R ¹ is C _1-3 fluoroalkyl. In certain embodiments, R ¹ is difluoromethyl or trifluoromethyl. In certain embodiments, R ¹ is difluoromethyl. In certain embodiments, R ¹ is trifluoromethyl.

In certain embodiments, R ² is hydrogen or alkyl.

In certain embodiments, R ² is hydrogen or C _1-6 alkyl.

In certain embodiments, R ² is hydrogen or C _1-3 alkyl.

In certain embodiments, R ² is alkyl. In certain embodiments, R ² is C _1-6 alkyl. In certain embodiments, R ² is C _1-3 alkyl. In certain embodiments, R ² is hydrogen.

In certain embodiments, R ¹ is hydrogen and R ² is alkyl. In certain embodiments, R ¹ is hydrogen and R ² is C _1-6 alkyl. In certain embodiments, R ¹ is hydrogen and R ² is C _1-3 alkyl.

In certain embodiments, R ¹ and R ² together with the atoms attached thereto form an aryl or cycloalkyl ring. In certain embodiments, R ¹ and R ² together with the atoms attached thereto form an aryl ring. In certain embodiments, R ¹ and R ² together with the atoms attached thereto form a cycloalkyl ring.

In certain embodiments, R ⁴ is alkyl or cycloalkyl.

In certain embodiments, R ⁴ is C _1-4 alkyl or C _3-5 cycloalkyl.

In certain embodiments, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is C _3-5 cycloalkyl. In certain embodiments, R ⁴ is cyclopentyl. In certain embodiments, R ⁴ is cyclobutyl. In certain embodiments, R ⁴ is cyclopropyl.

In certain embodiments, each R ⁶ is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxy.

In certain embodiments, each R ⁶ system is independently hydrogen, halogen, or cyano.

In certain embodiments, each R ⁶ is independently hydrogen, chloro, fluoro, or cyano.

In certain embodiments, each R ⁶ is independently hydrogen, fluoro, or cyano.

In certain embodiments, each R ⁶ series is independently hydrogen, or halogen.

In certain embodiments, each R ⁶ system is independently hydrogen, chloro, or fluoro.

In certain embodiments, each R ⁶ system is independently hydrogen or fluoro.

In certain embodiments, each R ⁶ system is independently hydrogen or cyano.

In certain embodiments, each R ⁶ is halogen. In certain embodiments, each R ⁶ is chloro or fluoro. In certain embodiments, each R ⁶ is fluoro. In certain embodiments, each R ⁶ is cyano.

In certain embodiments, A is CR ⁵ and R ⁵ is hydrogen, cyano, C _1-4 alkyl, or C _3-5 cycloalkyl.

In certain embodiments, A is N.

In some embodiments, no more than one of W, X, Y, and Z is N.

In certain embodiments, W, X, Y, and Z are each independently CR ⁶ .

In certain embodiments, Z is N.

In certain embodiments, the compound of formula I is a compound of formula Ia :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , A, X, and Z are each independently as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Ib :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , W, X, Y, and Z are each independently as defined herein.

In certain embodiments, the compound of formula I is a compound of formula Ic:

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , and Z are each independently as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Id :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ , and Z are each independently as defined herein.

In certain embodiments, a compound of formula I is a compound of formula Ie : [Formula Ie]

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , R ⁶ and Z are each independently as defined herein.

In certain embodiments, a compound of formula I is a compound of formula If :

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , And R ⁶ are each independently as defined herein.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen or halo, wherein at least one R ⁶ is halo .

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is C _1-4 alkyl or C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen, halo, Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is cycloalkyl; and each R ⁶ is independently a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen, cyano, or halo; and R ¹ is hydrogen , Halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen or halo, wherein at least one R ⁶ is halo; And R ¹ is hydrogen, halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen or halo, wherein at least one R ⁶ is halo; In addition, R ¹ is a cycloalkyl group optionally substituted, an aryl group optionally substituted, a heteroaryl group optionally substituted, or a heterocycloalkyl group optionally substituted.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen or halogen Group, wherein at least one R ⁶ is halo.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently halo.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen or halogen Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is an alkyl or cycloalkyl group; and each R ⁶ is independently hydrogen, halo, or Cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _1-4 alkyl group or a C _3-5 cycloalkyl group; and each R ⁶ is independent Ground is hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a cycloalkyl group; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently hydrogen, halo, Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a cycloalkyl group; and each R ⁶ is independently a halo group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently a halo group.

In certain embodiments, a compound of formula I is a compound of formula Ig : [Formula Ig]

Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof, wherein R ¹ , R ⁴ , And R ⁶ are each independently as defined herein.

In certain embodiments, the aforementioned compounds of formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen or halo, and at least one of R ⁶ is halo .

In certain embodiments, the aforementioned compounds of formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently halo.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is C _1-4 alkyl or C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen, halo, Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is cycloalkyl; and each R ⁶ is independently hydrogen or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is cycloalkyl; and each R ⁶ is independently a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently a halogen group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen, cyano, or halo; and R ¹ is hydrogen , Halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen or halo, and at least one R ⁶ is halo; And R ¹ is hydrogen, halogen, cyano, fluorenyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f O.

In certain embodiments, the compounds of the above formula Ig are their compounds, wherein: R ⁴ is alkyl or cycloalkyl; each R ⁶ is independently hydrogen or halo, and at least one R ⁶ is halo; In addition, R ¹ is a cycloalkyl group optionally substituted, an aryl group optionally substituted, a heteroaryl group optionally substituted, or a heterocycloalkyl group optionally substituted.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is alkyl or cycloalkyl; and each R ⁶ is independently hydrogen or halogen Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is alkyl or haloalkyl; R ⁴ is C _1-4 alkyl or C _3-5 cycloalkyl; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is an alkyl or cycloalkyl group; and each R ⁶ is independently hydrogen, halo, or Cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _1-4 alkyl group or a C _3-5 cycloalkyl group; and each R ⁶ is independent Ground is hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a cycloalkyl group; and each R ⁶ is independently hydrogen, halo, or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently hydrogen, halo, Or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a cycloalkyl group; and each R ⁶ is independently hydrogen or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently hydrogen or cyano.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a cycloalkyl group; and each R ⁶ is independently a halo group.

In certain embodiments, the compounds of the above formula If are their compounds, wherein: R ¹ is a haloalkyl group; R ⁴ is a C _3-5 cycloalkyl group; and each R ⁶ is independently a halo group.

In certain embodiments, the compound of formula I is a compound selected from the group consisting of 1-cyclopropyl-6-fluoro-2- (pyridazin-4-yl)- 1 H -benzo [ d ] imidazole (1); 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carbonitrile (2) ; 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole (3); 1-cyclopropyl-6-fluoro-2- (6-Vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (4); 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole-2 -Yl) pyrazine-3-carboxylic acid methyl ester (5); 1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole ( 6); 1- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl 1-ol (7); N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane Hydrazine (8); ((5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) carbamate ethyl ester ( 9); 4- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) morpholine (10); 1 -Cyclopropyl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin) -1-yl) pyrazin-4-yl) -1 H -benzo [ d ] Imidazole (11 ); 2- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) propan-2-ol (12); 5- (l-cyclopropyl-6-fluoro -1 H - benzo [d] imidazol-2-yl) - N - (tetrahydro -2H- pyran (pyran) -4- yl) pyridazin-3-amine (13); 4- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) cinnoline (14); 1-cyclopropyl-6-fluoro- 2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (15); N- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethanesulfonamide (16); 2- (6-chloropyrazin-4-yl) -1-ethyl- 1H -benzo [ d ] Imidazole-6-carbonitrile (17); 2- (4- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) Piperazin-1-yl) -N-isopropylacetamidamine (18); 1-cyclopropyl-5,6-difluoro-2- (6-methylpyrazin-4-yl) -1 H -Benzo [ d ] imidazole (19); 2- (4- (5- (1-cyclopropyl-6-fluoro-1 H ) -benzo [ d ] imidazol-2-yl) pyridazin-3-yl ) Piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (20); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ) imidazol-2-yl) -N-methylpyridazin-3-amine (21); 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro- 1 H -benzo [ d ] imidazole (22); 1-cyclopropyl-5,6-difluoro-2- (6-methoxypyrazine-4 -Yl) -1 H -benzo [ d ] imidazole (23); 1-cyclopropyl-5,6-difluoro-2- (6-isopropoxypyrazin-4-yl) -1 H- Benzo [ d ] imidazole (24); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N, N-dimethylpyrazine 3-Amine (25); 1-ethyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (26); 1-cyclopropyl-5,6 -Difluoro-2- (6- (2,2,2-trifluoroethoxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (27); 5- (1-cyclopropane -5,6-difluoro -1 H - benzo [d] imidazol-2-yl) - N - (2- methoxyethyl) pyridazin-3-amine (28); 1-cyclopropyl -2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (29); 1-cyclopropyl-6-fluoro-2- (6- Methylpyrazin-4-yl) -1 H -indole (30); N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) Pyrazin-3-yl) methyl) ethanesulfonamide (31); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N -(2,2,2-trifluoroethyl) pyridazin-3-amine (32); 1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -5,6-difluoro -1 H -benzo [ d ] imidazole (33); 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (34 ); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6 -Nitrile (35); 1-cyclopropyl-5,6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (36); 1- (4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl ) Piperazin-1-yl) ethan-1-one (37); 1-cyclopropyl-5,6-difluoro-2- (6- (4- (methylsulfonyl) piperazine-1- Yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (38); 4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] Imidazol-2-yl) pyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (39); 1-ethyl-2- (6-methoxypyridazin-4-yl) -1 H -Benzo [ d ] imidazole-6-carbonitrile (40); 1-ethyl-2- (6-ethylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (41); 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (42); 2 -(6-cyclobutoxytrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (43); 1-cyclopropyl-2- (6- (4,4-difluoropiperidin-1-yl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (44); 5-chloro-3 -Cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (45); 1-cyclopropyl-2- (6- (3 , 3-difluoropyrrolidin-1-yl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (46); 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2 -Trifluoroethyl-1-ol (47); 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3- ) -N, N-dimethylpyrrolidin-3-amine (48); 1-cyclopropyl-5,6-difluoro-2- (6- (4-fluorophenyl) pyridazine-4- ) -1 H -benzo [ d ] imidazole (49); 1-cyclopropyl-5,6-difluoro-2- (6-((4-fluorophenyl) ethynyl) pyridazine-4- ) -1 H -benzo [ d ] imidazole (50); 1-cyclopropyl-5,6-difluoro-2- (6-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (51); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl ) Ethylsulfonamide (52); 1-cyclopropyl-5,6-difluoro-2- (6-((1,1,1-trifluoroprop-2-yl) oxy) pyridazine- 4-yl) -1 H -benzo [ d ] imidazole (53); 3-cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] Pyridine-5-carbonitrile (54); 1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (55); 1- Cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -4- (trifluoromethyl) -1 H -benzo [ d ] imidazole (56); 1-cyclopropyl- 2- (6- (2,2-difluoropropoxy) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (57 ); 1-cyclopropyl-5,6-difluoro-2- (5-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (58); 1-cyclopropyl- 2- (6-cyclopropylpyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (59); 2- (6-chloropyridazin-4-yl)- 3-cyclopropyl-5-methoxy- 3H -imidazo [4,5- b ] pyridine (60); 1-cyclopropyl-5,6-difluoro-2- (6- (4- Fluoro-2-methylphenyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (61); 1-cyclopropyl-2- (6- (2,4-difluorophenyl) ) Dazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (62); 1-cyclopropyl-2- (6- (3,4-difluorophenyl) Pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (63); 1- (5- (1-cyclopropyl-5,6-difluoro-1 H- Benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one (64); 2- (6-chloropyrazin-4-yl) -1-ethyl-5,6- Difluoro-1 H -benzo [ d ] imidazole (65); 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole -6-carbonitrile (66); 2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole ( 67); 2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (68); 2- (6- (difluoromethyl) ) Dazin-4-yl) -1-ethyl- 1H -benzo [ d ] imidazole-6-carbonitrile (69); 1-cyclopropyl -2- (6- (1,1-difluoroethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (70); 1-cyclopropyl- 5,6-difluoro-2- (6- (2,2,2-trifluoroethyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (71); 2- (6- Cyclopropylpyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (72); 5-chloro-3-cyclopropyl-2- (6 -(Difluoromethyl) pyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (73); 1-cyclopropyl-5,6-difluoro-2- (5- Methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (74); 1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (75); 3-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -3 H -imidazo [4,5- b ] Pyridine-5-carbonitrile (76); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl ) Methyl) methanesulfonamide (77); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3 -Yl) methyl) -N -methylmethanesulfonamide (78); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole-2 -Yl) pyridazin-3-yl) methyl) propane-2-sulfonylamine (79); 1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfonyl) yl) Azin-4-yl) -1 H -benzo [ d ] imidazole (80); 1-cyclopropyl-2- (6- (Ethylsulfonyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (81); 1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfinamilide) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (82); 1-cyclopropyl-2- (6- (ethylsulfinylsulfenyl) ) Dazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (83); 5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazine- 4-yl) -3 H -imidazo [4,5- b ] pyridine (84); 1-cyclopropyl-5,6-difluoro-2- (6- (trifluoromethyl) pyridazine-4 -Yl) -1 H -benzo [ d ] imidazole (85); 1-cyclopropyl-2- (6- (trifluoromethyl) pyrazin-4-yl) -1 H -benzo [ d ] Imidazole-6-carbonitrile (86); 3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (87); 2-((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) isotetra Hydrothiazole 1,1-dioxide (88); 3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] Pyridine-5-carbonitrile (89); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -6- (trifluoromethyl) -1 H -benzo [ d ] imidazole ( 90); N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethyl) methyl Sulfonamide (91); 1-cyclopropyl-5,6-di 2- (6- (fluoromethyl) pyridazine-4-yl) -1 H - benzo [d] imidazole (92); 1-cyclopropyl-2- (5,6-dimethyl-pyridazine -4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (93); (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] Imidazol-2-yl) pyridazin-3-yl) methanol (94); 5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -Imidazo [4,5- b ] pyridine (95); N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazol-2-yl ) Dazin-3-yl) ethyl) ethanesulfonamide (96); 2- (6-butyldazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H- Benzo [ d ] imidazole (97); 1-cyclopropyl-6-methyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (98); 1 -Cyclopropyl-5,6-difluoro-2- (3-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (99); 1-cyclopropyl-2- (3 , 6-dimethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (100); 1-cyclopropyl-2- (6- (difluoromethyl) ) Dazin-4-yl) -6,7-difluoro-1 H -benzo [ d ] imidazole (101); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-thiol (102); 2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1-methyl -1 H -benzo [ d ] imidazole (104); 2- (6- (difluoromethyl) pyridazine-4- ) -5,6-difluoro-1-propyl-1 H -benzo [ d ] imidazole (105); 4- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ) imidazol-2-yl) -5,6,7,8-tetrahydrophosphonium (106); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzene and [d] imidazole-5-carbonitrile (example 107); l-cyclobutyl-5,6-difluoro-2- (6-methyl-pyridazine-4-yl) -1 H - benzo [d ] Imidazole (108); 1-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-ol (109); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid (110); 1-cyclopropyl-7-fluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (111); 5-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (112); 4-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (113 ); 1-cyclopropyl-5,6-difluoro-2- (6- (methoxymethyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (114); 5- (6-Cyano-1-cyclopropyl-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (115); 5- (6-cyano-1-cyclopropane yl -1 H - benzo [d] imidazol-2-yl) pyridazin-3-carboxylic acid (116); 1-cyclopropyl-2- (6- (cyclopropylmethoxy) -4- pyridazine ) -5,6-difluoro-1 H -benzo [ d ] Imidazole (117); 1-cyclopropyl-2- (6- (2,2,2-trifluoroethoxy) pyrazin-4-yl) -1 H -benzo [ d ] imidazole-6- Nitrile (118); 6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -5-fluoro-1 H -benzo [ d ] imidazole (119 ); 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1 H -benzo [ d ] imidazole-6-carbonitrile (120); 4 -(1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -6,7-dihydro-5 H -cyclopenta [ c ] pyrazine (121) ; 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole (122); 1-cyclopropyl-5 , 6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (123); 1-cyclopropyl-5,6-difluoro -2- (6- (isopropylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (124); 1-cyclopropyl-2- (6-((difluoromethyl) Yl) thio) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (125); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-ol (126); 1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -5 1,6-difluoro-1 H -benzo [ d ] imidazole (127); 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole-2- Yl) pyrazin-3-yl) ethan-1-ol (128); 1-cyclopropyl-5,6 -Difluoro-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (129); 1-cyclopropyl-5,6-difluoro- 2- (6-((trifluoromethyl) thio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (130); 1-cyclopropyl-2- (6- (difluoro (Methyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (131); 2- (6- (difluoromethyl) pyridazin-4-yl) -1-propyl-1 H -Benzo [ d ] imidazole (132); 1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-methyl Nitrile (133); 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -indole-3-carbonitrile (134); 2- (6- ( Difluoromethyl) pyridazin-4-yl) -1-methyl- 1H -indole-3-carbonitrile (135); 1-cyclopropyl-2- (6- (1-fluoroethyl) Pyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (136); its pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates Compounds, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs.

In another aspect, 2- (6- (Difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (103), or a medicament thereof is provided. Scientifically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

In one aspect, the compound of formula I is the other in which the compound inhibits (or is identified to inhibit) aldosterone synthase (CYP11B2).

Compounds herein include those compounds in which the compound is identified as having at least partially affinity for metalloenzymes by forming one or more of the following types of chemical interactions or bonds with metals: gamma bonds, covalent bonds , Coordination covalent bond, ionic bond, π bond, δ bond, or feedback bonding interaction. These compounds can also gain affinity through weaker interactions with metals such as Van der Waals interactions, π-cation interactions, π-anion interactions, dipole-dipole interactions, ion- Dipole interaction. In one aspect, the compound is identified as having a bonding interaction with a metal via a pyridazine moiety.

Methods for assessing metal-ligand binding interactions are known in the art, as exemplified in references including, for example: "Principles of Bioinorganic Chemistry", Lippard and Berg, University Science Books , (1994); "Mechanisms of Inorganic Reactions", Basolo and Pearson John Wiley & Sons Inc; 2nd Edition (September 1967); "Biological Inorganic Chemistry", Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, University Science Books (2007); Xue et al. "Nature Chemical Biology", Volume 4, Issue 2, 107-109 (2008).

In another aspect, a pharmaceutical composition is provided comprising a compound of formula I and a pharmaceutically acceptable carrier.

In another aspect, a method is provided for modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

In another aspect, a method of treating a subject suffering from or susceptible to a disorder or disease is provided, wherein the subject has been identified as in need of treatment of the disorder or disease, the methods comprising providing to the subject in need thereof An effective amount of a compound of formula I or a pharmaceutical composition is administered to allow the subject to treat the condition.

In another aspect, the subject is an animal different from a human.

In another aspect, a method is provided for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

In another aspect, a method is provided for treating a subject suffering from or susceptible to a metalloenzyme related disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme related disorder or disease, the methods comprising The subject is administered an effective amount of a compound of formula I or a pharmaceutical composition to enable the subject to treat the condition.

In another aspect, a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease is provided, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the methods comprising It is necessary for the subject to administer an effective amount of a compound of Formula I or a pharmaceutical composition such that the metalloenzyme activity in the subject is modulated (eg, down-regulated, inhibited).

The methods herein include those in which the disease or condition is mediated by any of the following: aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), nitric oxide synthesis Members of the enzyme family, thrombin synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-dissociating enzyme (CYP17), cytochrome P450 2A6 (CYP2A6), blood matrix oxygenase, Indoleamine 2,3-dioxidase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).

The methods herein include methods in which the disease or condition is one of the following: cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease , Urological diseases, or gastrointestinal diseases.

The methods herein include those in which the disease or condition is one of the following: hypertension, tolerant hypertension, morbidities associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, high pulmonary arteriality Blood pressure, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, Nephropathy, post-myocardial infarction, coronary heart disease, fibrosis, diseases characterized by increased collagen formation, fibrosis accompanied by hypertension and matrix remodeling, fibrosis accompanied by abnormal endothelial cell function, and Matrix remodeling, cardiovascular diseases such as atherosclerosis, atrial fibrillation, abnormal kidney function, liver disease, nonalcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis , Vascular fibrosis, myocardial necrotic lesions, vascular destruction, myocardial infarction, left ventricular hypertrophy, vascular wall Large, thickened endothelium, arterial fibrous necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, renal syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep Apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic kidney disease, or stroke.

The methods described herein include other methods in which the subject is identified as needing a particular specified treatment. Identifying a subject in need of such treatment may be at the judgment of the subject or a healthcare professional and may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[Definition]

In order that the invention may be more readily understood, certain terms are first defined herein for convenience.

As used herein, the term "treating" a disorder encompasses preventing, ameliorating, alleviating, and / or controlling the disorder and / or conditions that can cause the disorder. The terms "treating" and "treatment" refer to a method of reducing or alleviating a disease and / or its accompanying symptoms. According to the present disclosure, "treatment" includes preventing, blocking, inhibiting, attenuating, protecting, modulating, reversing the effects of a condition and reducing the occurrence of, for example, a harmful effect of a condition.

As used herein, "inhibition" encompasses preventing, reducing, and stopping processes. It should be noted that "enzyme inhibition" (eg, metalloenzyme inhibition) is differentiated and described below.

The term "modulating" refers to increasing or decreasing the activity of an enzyme in response to exposure to a compound of the present disclosure.

The terms "isolated", "purified" or "biologically pure" refer to a material that is substantially or substantially free of components that normally accompany it when found in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular, in each embodiment, the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The term "administration" or "administering" includes the pathway of introducing a compound to a subject to perform its desired function. Examples of administration routes that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.

The term "effective amount" includes an amount effective to achieve a desired result at a necessary dose and for a necessary period of time. The effective amount of the compound may vary depending on factors such as the subject's disease state, age, and weight, and the ability of the compound to elicit a desired response in the subject. The dosing regimen can be adjusted to provide the best therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are less important than the therapeutically beneficial effects.

As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean the administration of a compound, drug, or other material such that It enters the patient's system and is therefore subject to metabolism and other similar processes.

The term "therapeutically effective amount" refers to an amount of a compound that is administered sufficient to prevent the development of or reduce the one or more of the symptoms of the condition or disorder being treated.

A therapeutically effective amount (i.e., an effective dose) of a compound may vary within the range of about 0.005 μg / kg to about 200 mg / kg of body weight, preferably about 0.01 mg / kg to about 200 mg / kg, and more preferably about 0.015 mg / kg to about 30 mg / kg. In other embodiments, the therapeutically effective amount may vary from about 1.0 pM to about 10 μM. Skilled artisans will understand that certain factors can affect the dosage required to effectively treat a subject, including but not limited to the severity of the disease or condition, previous treatment, the general health and / or age of the subject And other diseases that exist. In addition, treating a subject with a therapeutically effective amount of a compound can include a single treatment or preferably can include a series of treatments. In one example, a compound in a range between about 0.005 μg / kg to about 200 mg / kg of body weight is used, between about 1 to 10 weeks, preferably between about 2 to 8 weeks, and more preferably The subjects are treated once a day between about 3 to 7 weeks and even more preferably for about 4, 5, or 6 weeks. In another example, the subject may be treated daily for several years in a chronic condition or condition scenario. It should also be understood that an effective dose of a compound for use in therapy may be increased or decreased during the course of a particular treatment.

The term "palm" refers to a molecule having the property of non-superimposability of a mirror partner, and the term "non-palm" refers to a molecule that can be superimposed on its mirror partner.

The term "non-mirromeric isomer" refers to a stereoisomer having two or more centers of asymmetry and whose molecules are not mirror images of one another.

The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

The terms "isomers" or "stereoisomers" refer to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.

The term "prodrug" includes compounds that have a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized into active drugs in vivo by esterases or by other mechanisms. Examples of prodrugs and their uses are well known in the art (see, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of a compound, or by reacting a purified compound in its free acid form or hydroxyl group with a suitable esterifying agent alone. Hydroxyl groups can be converted to esters by treatment with carboxylic acids. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkyl alkenyl esters, di-lower alkyl-amino lower alkyl esters (E.g., dimethylaminoethyl), fluorenyl lower alkyl (e.g., ethoxymethyl), fluorenyl lower alkyl (e.g., trimethylacetoxymethyl) Esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl Alkyl-lower alkyl esters, amidines, lower alkyl amidos, di-lower alkyl amidos, and hydroxy amidos. Preferred prodrug moieties are propionate and fluorenyl ester. It also includes prodrugs that are converted into the active form in vivo via other mechanisms. In various aspects, the compounds of the present disclosure are prodrugs having any of the formulae herein.

The term "subject" refers to an animal such as a mammal, including but not limited to primates (e.g., humans), dairy cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and similar animals . In certain embodiments, the subject is a human.

When used in this application including in the scope of a patent application, the terms "a (an / an)" and "the" shall mean "one or more (species)". Thus, for example, a reference to "the same" includes a plurality of samples, unless the context is clearly contrary (e.g., a plurality of samples), and so on.

Throughout this specification and the scope of the patent application, the term "comprise / comprises / comprising" is used in a non-exclusive sense, unless the context requires otherwise.

As used herein, the term "about" when referring to a value is intended to cover from a specified amount of ± 20% in some embodiments, ± 10% in some embodiments, ± 5% in some embodiments, in some embodiments Variations of ± 1% in the examples, ± 0.5% in some embodiments, and ± 0.1% in some embodiments, therefore, the variations are suitable for performing the disclosed method or using the disclosed composition.

The use of the term "inhibitor" herein is intended to mean a molecule exhibiting an activity for inhibiting metalloenzymes. "Inhibition" herein is intended to reduce the activity of metalloenzymes. This decrease is compared to the activity of metalloenzymes in the absence of inhibitors. In some embodiments, the term "inhibition" means a reduction in metalloenzyme activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least About 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition means a reduction in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition means a reduction in metalloenzyme activity of about 95% to 100%, for example, a reduction in activity is 95%, 96%, 97%, 98%, 99%, or 100%. This reduction can be measured using a variety of techniques that will be recognized by those skilled in the art. Specific assays for measuring individual activities are described below.

In addition, the compounds of this disclosure include olefins having any geometry: "Z" refers to a geometry called a "cis" (same side) configuration, and "E" refers to a "trans" (opposite side) ) Configuration geometry. In contrast to the nomenclature of palm centers, the terms "d" and "l" are defined by the recommendations of the International Union of Pure and Applied Chemistry (IUPAC). With regard to the use of the terms non-mirror isomers, racemates, epimers and enantiomers, these terms will be used in their normal context to describe the stereochemistry of the formulation.

As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, third butyl, and n-pentyl. The alkyl group may be optionally substituted with one or more substituents.

The term "haloalkyl" refers to an alkyl group substituted with one or more halo substituents. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, bromoethyl, chloroethyl, and 2,2,2-trifluoroethyl.

The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl may be optionally substituted with one or more substituents.

The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, where sp ^{2 of the} alkenyl unit is mixed into one of the carbons Or more are attached to the aryl moiety. The alkenyl may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl is optionally substituted with one or more substituents.

The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, wherein the sp of the alkynyl unit is mixed into one of the carbons or Many are attached to the aryl moiety. The alkynyl is optionally substituted with one or more substituents.

The sp ² or sp carbon of an alkenyl group and an alkynyl group may be a connection point of an alkenyl group or an alkynyl group, respectively, as required.

The term "alkoxy" refers to an -O-alkyl substituent.

As used herein, the terms "halogen", "halo" or "halo" mean -F, -Cl, -Br or -I.

The term "alkylthio" refers to an -S-alkyl substituent.

The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

The term "haloalkoxy" refers to -O-alkyl substituted with one or more halo substituents. Examples of haloalkoxy include trifluoromethoxy and 2,2,2-trifluoroethoxy.

The term "haloalkoxyalkyl" refers to -alkyl-O-alkyl 'wherein alkyl' is substituted with one or more halo substituents.

The term "haloalkylaminocarbonyl" refers to -C (O) -amino-alkyl, wherein the alkyl is substituted with one or more halo substituents.

The term "haloalkylthio" refers to -S-alkyl substituted with one or more halo substituents. Examples of haloalkylthio include trifluoromethylthio and 2,2,2-trifluoroethylthio.

The term "haloalkylcarbonyl" refers to a -C (O) -alkyl group substituted with one or more halo substituents. Examples of haloalkylcarbonyl include trifluoroethylfluorenyl.

The term "cycloalkyl" refers to a 3- to 8-membered monocyclic hydrocarbon or 7 to 14-membered bicyclic ring system of a hydrocarbon having at least one saturated ring or at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. The cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like Group.

The term "cycloalkoxy" refers to a -O-cycloalkyl substituent.

The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

The term "cycloalkylaminocarbonyl" refers to a -C (O) -NH-cycloalkyl substituent.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. The aryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of the aryl group may be substituted by a substituent. Examples of aryl include phenyl, naphthyl, allyl, fluorenyl, indenyl, azulenyl, and the like.

The term "aryloxy" refers to an -O-aryl substituent.

The term "aralkoxy" refers to an -O-alkyl-aryl substituent.

The term "aralkylthio" refers to an -S-alkyl-aryl substituent.

The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

The term "aralkylaminocarbonyl" refers to a -C (O) -amino-alkyl-aryl substituent.

The term "aralkylsulfonyl" refers to a -S (O) ₂ -alkyl-aryl substituent.

The term "aralkylsulfinylene" refers to an -S (O) -alkyl-aryl substituent.

The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

The term "alkaryl" refers to an -aryl-alkyl substituent.

The term "aralkyl" refers to an -alkyl-aryl substituent.

The term "heteroaryl" refers to an aromatic 5 to 8 member having 1 to 4 ring heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic. Monocyclic, 8 to 12-membered bicyclic or 11 to 14-membered tricyclic ring systems, such heteroatoms are selected from O, N or S and the remaining ring atoms are carbon (with the appropriate hydrogen atom unless otherwise indicated). Heteroaryl is optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazole , Isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

The term "heteroaryloxy" refers to a -O-heteroaryl substituent.

The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

The term "nitrogen-containing heteroaryl" refers to a hetero ring having 1 to 4 ring nitrogen heteroatoms if monocyclic, 1 to 6 ring nitrogen heteroatoms if bicyclic, or 1 to 9 ring nitrogen heteroatoms if tricyclic. Aryl.

The term "heterocycloalkyl" means a non-aromatic 3 to 8 member containing 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic. Monocyclic, 7 to 12-membered bicyclic or 10 to 14-membered tricyclic ring systems, where these heteroatoms are selected from O, N, S, B, P, or Si, where the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyls include piperidinyl, piperazinyl, tetrahydropiperanyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane (1 , 3-dioxolane), tetrahydrofuranyl, tetrahydrothienyl, thirenyl, and the like.

The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

The term "alkylamino" refers to an amine substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent that is further substituted with one or more amine groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. Alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl and alkylcarbonylaryl alkyl or aryl groups Some are optionally substituted with one or more substituents.

Acids and bases suitable for the methods herein are known in the art. An acid catalyst is any acidic chemical that can be inorganic (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoromethanesulfonic acid) Acid 镱). Acids are used in catalytic or stoichiometric amounts to promote chemical reactions. A base is any basic chemical that can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are used in catalytic or stoichiometric amounts to promote chemical reactions.

An alkylating agent is any agent capable of alkylating a functional group of interest (eg, an oxygen atom of an alcohol, a nitrogen atom of an amine group). Alkylating agents are known in the art, including in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide, or benzyl chloride), Alkyl sulfate (eg, methyl sulfate) or other alkyl-leaving group combinations known in the art. Leaving groups are any stable species that can leave the molecule during a reaction (e.g., elimination reaction, substitution reaction) and are known in the art, including in the references cited herein, And include halides (e.g., I-, Cl-, Br-, F-), hydroxy, alkoxy (e.g., -OMe, -Ot-Bu), fluorenyl anions (e.g., -OAc, -OC ( O) CF _3), sulfonates (e.g., methanesulfonate acyl, acyl toluenesulfonyl), acetyl amine (e.g., -NHC (O) Me), carbamate (e.g., N (Me) C ( O) Ot-Bu), phosphate (for example, -OP (O) (OEt) ₂ ), water or alcohol (protonic conditions), and the like.

In certain embodiments, on any group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) The substituent may be at any atom of the other group, which may be any substituted group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl (Cycloalkyl, cycloalkyl, heterocycloalkyl) may be optionally substituted with one or more substituents (which may be the same or different), and each substituent replaces a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano Alkyl, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, pendant (i.e., carbonyl), carboxy, methyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkyl Carbonylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amine, aminoalkyl, dialkylamino , Alkylcarbonylamino, aminoaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or aryl substituted with arylamino; Aralkylamino, aralkylaminocarbonyl, fluorenylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, Arylsulfoamidoamino, imino, formamido, ureido, carbamoyl, thioureido, cyanothio, sulfoamido, sulfoamidoalkyl, sulfoamidoaryl, Mercaptoalkoxy, N-hydroxyfluorenyl Or N'-aryl, N "-hydroxyfluorenyl.

The compounds of this disclosure can be made by means known in the art of organic synthesis. Methods for optimizing reaction conditions where necessary to minimize competing by-products are known in the art. Reaction optimization and scaling can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (for example, Design And Optimization in Organic Synthesis, 2nd edition , Carlson R, 2005; Elsevier Science Ltd .; Jähnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004 43 : 406; and references therein). Additional reaction protocols and protocols can be used by skilled artisans using searchable commercially available database software such as SciFinder® (CAS Division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by using This is determined by an appropriate keyword search, such as a Google® Internet search engine or a keyword database such as the US Patent and Trademark Office text database.

As will be understood by those skilled in the art, methods for synthesizing compounds of the formulae herein will be apparent to those of ordinary skill, including the methods in the schemes and examples herein. In addition, various synthetic steps can be performed in place of sequence or order to obtain the desired compound. In addition, the solvents, temperatures, reaction durations, etc. described herein are for illustration purposes only, and those of ordinary skill will recognize that changes in reaction conditions can produce the desired compounds of this disclosure.

The compounds herein may also contain linkages (e.g., carbon-carbon bonds) in which the rotation of the bond is restricted around that particular linkage, such as a restriction caused by the presence of a ring or double bond. Therefore, all cis / trans and E / Z isomer systems are explicitly included in this disclosure. The compounds herein may also be represented in multiple tautomeric forms, in which case the present disclosure explicitly includes tautomeric forms of the compounds described herein, even if only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in this disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in this disclosure. Also included are extracts and fractions of compounds containing the present disclosure. The term isomers is intended to include non-mirror isomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers and similar isomers. For compounds containing one or more stereoisomeric centers, such as palm compounds, the methods of the present disclosure can be performed using mixtures of enantiomerically enriched compounds, racemates, or non-image isomers .

Preferably, the enantiomerically enriched compound has an enantiomeric excess of 50% or more, and more preferably, the compound has 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more Enantiomeric excess. In a preferred embodiment, only the enantiomers or non-mirror isomers of the palmar compounds of the present disclosure are administered to a cell or subject.

[treatment method]

In one aspect, a method is provided for treating a subject suffering from or susceptible to a disorder or disease, the method comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

In other aspects, a method is provided for treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the method comprising administering to the subject in need thereof A subject is administered an effective amount of a compound of formula I or a pharmaceutical composition to enable the subject to treat the condition.

In one aspect, a method is provided for modulating metalloenzyme activity in a cell of a subject, the method comprising contacting the subject with a compound of formula I in an amount sufficient to modulate metalloenzyme activity and at a level sufficient to modulate metal Enzyme activity.

In one embodiment, the adjustment is inhibition.

In another aspect, a method is provided for treating a subject suffering from or susceptible to a metallozyme-mediated disorder or disease, the method comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

In other aspects, methods are provided for treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the method comprising The subject is administered an effective amount of a compound of formula I or a pharmaceutical composition to enable the subject to treat the condition.

In certain embodiments, methods are provided for treating a disease, disorder, or symptom thereof, wherein the disorder is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, Central nervous system (CNS) disease, urological disease, or gastrointestinal disease. In certain embodiments, the disease is hypertension, tolerant hypertension, pathologies associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic dysfunction, left Ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, posterior myocardial infarction, coronary heart disease, fibrosis Diseases characterized by increased collagen formation, fibrosis and matrix remodeling with hypertension, fibrosis and matrix remodeling with abnormal endothelial cell function, cardiovascular diseases such as atherosclerosis, atrial fibrillation, kidney Dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular destruction, myocardial infarction, left ventricle Hypertrophy, vascular wall hypertrophy, thickened endothelium, fibrous necrosis such as arteries, kidney disease, diabetic nephropathy Changes, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic Fatty liver disease, kidney disease, diabetic kidney disease, or stroke.

In certain embodiments, the subject is a mammal, preferably a primate or a human.

In another embodiment, a method as described above is provided, wherein an effective amount of a compound of formula I is as described above.

In another embodiment, a method as described above is provided, wherein the compound of formula I is administered intravenously, intramuscularly, subcutaneously, intraventricularly, orally or locally.

In another embodiment, a method as described herein is provided, wherein the compound of formula I demonstrates selectivity against a range of activity against the target enzyme (eg, aldosterone synthetase (CYP11B2) IC ₅₀ <1.0 μM).

In other embodiments, a method as described above is provided, wherein the compound of formula I is administered alone or in combination with one or more other therapeutic agents. In another embodiment, the additional therapeutic agent is an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an antiangiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent , Central nervous system (CNS) disease agent, urinary disease agent or gastrointestinal disease agent.

In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating kidney disease, an agent for treating congestive heart failure, An agent for treating atherosclerosis, an agent for treating diabetes, an agent for treating obesity, or an agent for treating metabolic diseases.

Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP) pairs Inhibitors, angiotensin II receptor blocker (ARB), mineralocorticoid receptor antagonist (MRA), neutral peptide endonuclease inhibitor (NEP), Enkephalinase inhibitors, calcium channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including Heinz ring diuretics), potassium channel activators, endothelin receptors Antagonists, endothelin 1 receptor antagonists, soluble guanylate cyclase stimulators, vasodilators HMG-CoA reductase inhibitors, nicotinic acid and nicotinic acid receptor antagonists, Nimman-Pick II C1-like 1 (Niemann-Pick C1-like 1; NPC1L1) inhibitors, insulin or insulin analogs, biguanides (eg, metformin), sulfonylureas, peroxisome proliferator-activated receptors ; PPAR) antagonists and including PPARγ Antagonists and some antagonists of other PPAR ligands, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1), GLP -1 receptor antagonist and sodium-glucose co-transporter 2 (SGLT2) inhibitor.

Another object of the present disclosure is the use of a compound (eg, a compound of formula I ) as described herein in the manufacture of a medicament suitable for treating a metalloenzyme-mediated disorder or disease. Another object of this disclosure is the use of a compound (eg, a compound of formula I ) as described herein for the treatment of a metalloenzyme-mediated disorder or disease. Another object of this disclosure is the use of a compound (eg, a compound of Formula I ) as described herein in the manufacture of an agronomic composition suitable for treating or preventing a metalloenzyme-mediated disorder or disease in an agronomic or agricultural context.

[Pharmaceutical composition]

In one aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

In another embodiment, a pharmaceutical composition is further provided that further comprises an additional therapeutic agent. In another embodiment, the additional therapeutic agent is an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an antiangiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent , Central nervous system (CNS) disease agent, urinary disease agent or gastrointestinal disease agent.

In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating kidney disease, an agent for treating congestive heart failure, An agent for treating atherosclerosis, an agent for treating diabetes, an agent for treating obesity, or an agent for treating metabolic diseases.

Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, dual inhibitors of angiotensin-converting enzyme (ACE), and neutral peptide endonuclease (NEP), Angiotensin II receptor blocker (ARB), mineral corticosteroid receptor antagonist (MRA), neutral peptide inhibitor (NEP), enkephalinase inhibitor, calcium channel blocker , Alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including Heinz ring diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor antagonists, soluble Guanylate cyclase stimulator, vasodilator HMG-CoA reductase inhibitor, nicotinic acid and nicotinic acid receptor antagonist, Niemann-Pick II C1-like 1 (NPC1L1) inhibitor, insulin or insulin Analogs, biguanides (e.g., metformin), sulfonylureas, peroxisome proliferators (PPAR) antagonists and some antagonists including PPARγ antagonists and other PPAR ligands, dipeptidyl peptidases -4 (DPP4) inhibitor, glucagon-like peptide 1 (GLP-1), GLP-1 receptor antagonist, and sodium-glucose cotransporter 2 ( SGLT2) inhibitor.

In one aspect, kits are provided, the kits comprising an effective amount of a compound of formula I in a unit dosage form together with instructions for administering the compound to a subject suffering from or susceptible to a metalloenzyme Mediates a disease or disorder, including cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease. In other embodiments, the disease, disorder, or symptom thereof is hypertension, tolerant hypertension, pathologies associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary hypertension, heart failure, diastolic Dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, posterior myocardial infarction, coronary heart Disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling with hypertension, fibrosis and matrix remodeling with abnormal endothelial cell function, such as atherosclerosis, atrial fibrillation Vascular disease, renal dysfunction, liver disease, nonalcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular destruction, myocardium Infarction, left ventricular hypertrophy, vascular wall hypertrophy, thickened endothelium, fibrous necrosis such as arteries, kidney disease Diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, liver cirrhosis, Non-alcoholic fatty liver disease, kidney disease, diabetic kidney disease, or stroke.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds, which salts are prepared using relatively non-toxic acids or bases, depending on the compounds described herein Specific substituents found above. When the compounds of this disclosure contain relatively acidic functionality, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, which is pure or soluble Suitable inert solvents. Examples of the pharmaceutically acceptable base addition salt include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an organic amine salt, or a magnesium salt or the like. When the compounds of the present disclosure contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, which is pure or soluble In a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include their acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, Dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid or phosphorous acid and similar acids, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid , Malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, amygdalic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids . Also included are salts of amino acids such as arginine and similar salts; and salts of organic acids such as glucuronic acid or galacturonic acid and similar acids (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionality, allowing the compounds to be converted into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in this disclosure.

The neutral form of a compound can be regenerated by contacting a salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of a compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt is equivalent to the parent form of the compound for the purposes of this disclosure.

In addition to salt forms, the present disclosure provides compounds in prodrug form. The compound prodrugs described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to disclosed compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can slowly convert to a disclosed compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent.

Certain compounds of the present disclosure may exist in unsolvated as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of this disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses covered by this disclosure and are intended to be within the scope of this disclosure.

This disclosure also provides pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, a compound of formula I is administered to a subject using a pharmaceutically acceptable formulation, such as, for example, administering a pharmaceutically acceptable formulation to a subject. The subject then provides the subject with continuous delivery of the compound for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks of a pharmaceutically acceptable formulation.

The actual dosage level and time course of the active ingredient administration in the pharmaceutical composition of the present disclosure may vary so that an amount of the active ingredient is obtained, which is effective to achieve the desired effect for a particular patient, composition, and mode of administration A therapeutic response is desired without toxicity (or unacceptable toxicity) to the patient.

In use, at least one compound according to the present disclosure is administered to a pharmaceutically effective amount in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous or intraventricular injection or by oral or local administration. Subjects in need. According to this disclosure, the compounds of this disclosure can be administered alone or in combination with a second, different therapeutic agent. "Combined" means together, substantially simultaneously, or sequentially. In one embodiment, a compound of the present disclosure is administered swiftly. The compounds of the present disclosure may thus be administered over a short course of treatment, such as from about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure may be administered over a longer period of time to ameliorate chronic conditions, such as, for example, about one to several months, depending on the condition to be treated.

"Pharmaceutically effective amount" as used herein means the amount of a compound of the present disclosure that is high enough to significantly positively improve the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk) Ratio), which is within the scope of perfect medical judgment. The pharmaceutically effective amount of the compounds of this disclosure will vary with the specific goals to be achieved, the age and physical condition of the patient to be treated, the severity of the underlying disease, the duration of treatment, the concurrent therapy used, and the nature of the specific compound . For example, a therapeutically effective amount of a compound of the present disclosure administered to a child or infant will be proportionately reduced based on sound medical judgment. An effective amount of a compound of this disclosure will therefore be the lowest amount that will provide the desired effect.

The determined practical advantage of this disclosure is that the compound can be administered in a suitable manner, such as by intravenous, intramuscular, subcutaneous, oral or intraventricular injection route, or by topical application, such as an emulsion or gel Agent for topical application. Depending on the route of administration, it may be necessary to coat the active ingredient of a compound comprising the present disclosure in a material to protect the compound from the effects of enzymes, acids, and other natural conditions that can inactivate the compound. In order to administer the compounds of the present disclosure in addition to parenteral administration, the compounds may be coated with or accompanied by a material that prevents passivation.

The compounds can be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

Some examples of substances that can act as pharmaceutical carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and acetic acid Cellulose; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols , Such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffers; skim milk powder; and, for example, used in pharmaceutical formulations Other non-toxic compatible substances, such as vitamin C, estrogen and violet marigold. Wetting agents and lubricants, such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, pastilles, stabilizers, antioxidants and preservatives may also be present. Solubilizers including, for example, cremaphore and β-cyclodextrin can also be used in the pharmaceutical compositions herein.

A pharmaceutical composition containing the target active compound (or a prodrug thereof) disclosed in the present disclosure can be manufactured by a conventional mixing, dissolving, granulating, sugar-coated tablet crushing, emulsifying, encapsulating, retaining or freeze-drying process. One or more physiologically acceptable carriers, diluents, excipients, or adjuvants may be used to formulate the composition in a conventional manner, which adjuvants facilitate the processing of the active compound into a pharmaceutically acceptable formulation.

The subject pharmaceutical composition disclosed in this disclosure may take a form suitable for virtually any mode of administration including, for example, topical, eye, oral, cheek, systemic, nasal, injection, transdermal , Transrectal, transvaginal, and similar modes, or may take forms suitable for administration by inhalation or insufflation.

For topical administration, the active compound or prodrug may be formulated as a solution, gel, ointment, emulsion, suspension, and the like.

Systemic formulations include those formulations designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, and for transdermal, transmucosal, oral or The lungs administer these designed formulations.

Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compounds in aqueous or oily vehicles. The composition may also contain formulation agents such as suspending, stabilizing and / or dispersing agents. Formulations for injection may be presented in unit dosage forms (for example, in ampoules or in multi-dose containers) and may contain added preservatives.

Alternatively, injectable formulations may be provided in powder form for rehydration with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffers, glucose solutions, and similar vehicles before use. To this end, the active compound may be dried by any technique known in the art, such as freeze drying, and reconstituted before use.

For transmucosal administration, penetrants suitable for the barrier to penetrate are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical composition may take the form of, for example, sugar tablets, lozenges, or capsules prepared by conventional means using pharmaceutically acceptable excipients such as a binder (e.g. , Pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or Silicon dioxide); disintegrants (for example, potato starch or starch sodium glycolate); or wetting agents (for example, sodium lauryl sulfate). Lozenges can be coated by methods well known in the art using, for example, sugar or enteric coating.

Liquid preparations for oral administration may take the form of, for example, tinctures, solutions, syrups or suspensions, or such liquid preparations may be present as dry products for rehydration with water or other suitable vehicle before use . Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example , Lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents, as appropriate.

Formulations for oral administration can be suitably formulated to obtain controlled release of the active compound or prodrug, as is well known.

For buccal administration, the composition may take the form of lozenges or lozenges formulated in a conventional manner.

For transrectal and transvaginal routes of administration, the active compounds can be formulated as solutions (for retaining enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound or prodrug may suitably be delivered in the form of an aerosol spray from a pressurized package or nebulizer by means of a suitable propellant, which propellant Examples include dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, fluorocarbons, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the metered amount. Capsules and cartridges suitable for use in an inhaler or insufflator (e.g., capsules and cartridges made of gelatin) can be formulated to contain a powder mixture containing a compound and a suitable powder base such as lactose or starch.

Specific examples of aqueous suspension formulations suitable for nasal administration using a commercially available nasal spray device include the following ingredients: active compound or prodrug (0.5-20 mg / ml); benzyl ammonium chloride (0.1- 0.2mg / mL); Polysorbate 80 (TWEEN ^® 80; 0.5-5mg / ml); Sodium carboxymethylcellulose or microcrystalline cellulose (1-15mg / ml); Phenylethanol (1-4mg / ml) ml); and dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted to vary from about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

For ocular administration, the active compound or prodrug may be formulated as solutions, emulsions, suspensions, and the like suitable for administration to the eye. Various vehicles suitable for administering the compound to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No. 6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No. 5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No. 5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; and U.S. Patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

For extended delivery, the active compound or prodrug can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredients can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or formulated as sparingly soluble derivatives, such as sparingly soluble salts. Alternatively, transdermal delivery systems manufactured as adhesive discs or patches that slowly release the active compound for transdermal absorption can be used. For this reason, penetration enhancers can be used to promote transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Patent No. 5,407,713; U.S. Patent No. 5,352,456; U.S. Patent No. 5,332,213; U.S. Patent No. 5,336,168; U.S. Patent No. 5,290,561; U.S. Patent No. 5,254,346; U.S. Patent No. 5,164,189 US Patent No. 5,163,899; US Patent No. 5,088,977; US Patent No. 5,087,240; US Patent No. 5,008,110; and US Patent No. 4,921,475, each of which is incorporated herein by reference in its entirety.

Alternatively, other medical delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds or prodrugs. Certain organic solvents such as dimethylsulfoxide (DMSO) can also be used.

If desired, the pharmaceutical composition may be present in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active compound. The package may, for example, contain metal or plastic foil, such as a blister package. The pack or dispenser device may be accompanied by instructions for administration.

The active compound or prodrug or composition thereof of the present disclosure will generally be used in an amount effective to achieve a desired result, such as an amount effective to treat or prevent a particular disease being treated. Compounds may be administered therapeutically to achieve a therapeutic benefit, or prophylactically to achieve a preventive benefit. Therapeutic benefit means eradication or improvement of the underlying condition being treated and / or eradication or improvement of one or more of the symptoms associated with the underlying condition so that the patient reports an improvement in the sense or condition, although the patient may still be affected by the underlying condition Torture. For example, administration of a compound to a patient suffering from an allergy is not only when the basic allergic reaction is eradicated or ameliorated, but after exposure to the allergen, the patient reports a decrease in severity or duration of symptoms associated with the allergy. Provides therapeutic benefits from time to time. As another example, therapeutic benefits in an asthma scenario include improved breathing after the onset of an asthma attack, or a reduction in the frequency or severity of an asthma event. Therapeutic benefits also include stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

For prophylactic administration, the compounds can be administered to patients at risk for one of the previously described diseases. A patient at risk of developing a disease may be a patient having characteristics that place the patient in a designated group of risk patients, which is defined by an appropriate medical professional or group. A patient at risk can also be a patient who is usually or routinely in a situation where the development of a basic disease can occur, which can be treated by administering a metalloenzyme inhibitor according to this disclosure. In other words, a patient at risk is a patient who is ordinarily or routinely exposed to a disease or disease-causing condition or who can be exposed acutely for a limited time. Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in patients diagnosed with a basic condition.

The amount of compound administered will depend on a variety of factors including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is preventive or curative, the severity of the indication being treated and the age and weight of the patient, the particular Bioavailability of active compounds and similar factors. The determination of an effective dose is well within the ability of those skilled in the art.

Effective doses can be estimated initially from in vitro analysis. For example, an initial dose suitable for use in an animal can be formulated to achieve a circulating blood or serum concentration of the active compound that is at or above the IC50 of a particular compound as measured in an in vitro assay such as an in vitro fungus MIC or MFC and other in vitro analyses described in the Examples section. It is well within the ability of a skilled artisan to calculate a dose that achieves such circulating blood or serum concentrations, taking into account the biological availability of a particular compound. For guidance, see Fingl & Woodbury, "General Principles", In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics , Chapter 1, pages 1-46, latest edition, Pagamonon Press and references cited therein, which are cited by reference and Included in this article.

The initial dose can also be estimated from in vivo data such as animal models. Animal models suitable for testing the efficacy of compounds for treating or preventing various diseases as described above are well known in the art.

The amount of dosage will typically range from about 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower, such It depends on the activity of the compound, its bioavailability, the mode of administration, and various factors discussed above, among other factors. The amount and interval of the dose can be individually adjusted to provide the plasma level of the compound, which is sufficient to maintain a therapeutic or prophylactic effect. Under conditions such as topical administration or selective absorption, the effective local concentration of the active compound cannot be related to the plasma concentration. Skilled artisans will be able to optimize effective topical doses without undue experimentation.

The compound may be administered once a day, several times or several times a day, or even multiple times a day, depending on the indication being treated and the judgment of the prescribing physician, among others.

Preferably, the compound will provide a therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of a compound can be determined using standard medical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred.

The recitation of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any one of the groups or combinations of listed groups. The description of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or part thereof. The description of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[Example]

In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not intended to be construed as limiting its scope in any way.

General experimental procedures

The definitions of the structure variables in the scheme in this paper are equivalent to those of the corresponding positions in the formulas described in this paper. Exemplary compounds listed in Table 2 were characterized by the HPLC and LCMS methods described in Table 1.

[General abbreviation:]

ACN Acetonitrile

br wide

d doublet

dd double doublet

dba dibenzylideneacetone

DIPEA diisopropylethylamine

dppf 1,1’-ferrocenediyl-bis (diphenylphosphine)

h hours

HRMS High Resolution Mass Spectrometry

HPLC

LCMS liquid chromatography and mass spectrometry

MS mass spectrometry

MW microwave

m multiplet

min minutes

mL ml

m / z mass-to-charge ratio

NMR

ppm parts per million

rt or RT room temperature

s unimodal

t triplet

TLC thin layer chromatography

[Preparation Int-1]

N-cyclopropyl -5-fluoro-2-nitroaniline

To a stirred solution of 2,4-difluoro-1-nitrobenzene (25 g, 157.23 mmol) in potassium fluoride (9.12 g, 157.23 mmol) under an inert atmosphere was added potassium carbonate (21.7 g, 157.23 mmol), followed by Instead, cyclopropylamine (10.75 g, 188.68 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the consumption of the starting material was proved by thin layer chromatography (TLC), the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (EtOAc) (2 x 200 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl -5-fluoro-2-nitroaminebenzene (26 g, 132.65 mmol) as a yellow solid. , 84%).

¹ H NMR (500MHz, CDCl ₃ ): δ 8.20 (dd, J = 9.3,6.1Hz, 1H), 6.95 (dd, J = 11.4,2.7Hz, 1H), 6.45-6.39 (m, 1H), 2.59- 2.53 (m, 1H), 0.97-0.92 (m, 2H), 0.71-0.65 (m, 2H).

N ¹ -cyclopropyl-5-fluorobenzene-1,2-diamine (Int-1)

To a stirred solution of N-cyclopropyl -5-fluoro-2-nitroaniline (24 g, 122.45 mmol) in methanol (MeOH) (300 mL) was added 10% Pd / C (50 % Wet, 2.4 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 8 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give N ¹ -cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (18 g, 108.43 mmol, 88%) as a brown slurry.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 6.52 (dd, J = 11.6, 2.8 Hz, 1H), 6.45 (dd, J = 8.4, 6.0 Hz, 1H), 6.18 (td, J = 8.5, 2.9 Hz, 1H), 5.28 (s, 1H), 4.30 (br s, 2H), 2.36-2.28 (m, 1H), 0.74-0.68 (m, 2H), 0.42-0.37 (m, 2H).

LC-MS: m / z 166.8 [M + H] ⁺ at 1.64 RT (72.46% purity).

[Preparation Int-2]

(5- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol

To methyl 5- (1-cyclopropyl-6-fluoro-1H-benzo [d] imidazol-2-yl) pyrazine-3-carboxylic acid (250 mg, 0.8 mmol) at 0 ° C under an inert atmosphere. To a stirred solution of a methanol / tetrahydrofuran (THF) (2: 1, 15 mL) mixture was added sodium borohydride (152 mg, 4.01 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain (5- (1-cyclopropyl-6-fluoro-1 H -benzo [d] imidazole-2- Yl) pyridazin-3-yl) methanol (130 mg, 0.46 mmol, 57%), which was used in the next step without further purification.

LC-MS: m / z 284.9 [M + H] ⁺ at 1.94 RT (72.20% purity).

5- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxaldehyde (Int-2)

To (5- (1-cyclopropyl-6-fluoro- 1H -benzo [d] imidazol-2-yl) pyridazin-3-yl) methanol (130 mg, 0.46) at 0 ° C under an inert atmosphere. mmol) in a stirred solution of CH ₂ Cl ₂ (10 mL) was added Dess-Martin periodinane (DMP) (291 mg, 0.69 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture (20mL) and quenched with saturated sodium bicarbonate solution and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d] as a brown solid ] Imidazol-2-yl) pyridazin-3-carboxaldehyde Int-2 (50 mg, 0.18 mmol, 39%).

¹ H NMR (500MHz, CDCl ₃ ): δ 10.50 (s, 1H), 10.06 (d, J = 2.0Hz, 1H), 8.64 (d, J = 2.3Hz, 1H), 7.80 (dd, J = 8.8, 4.8Hz, 1H), 7.34 (dd, J = 8.4, 2.3Hz, 1H), 7.13 (td, J = 9.3, 2.3Hz, 1H), 3.73-3.69 (m, 1H), 1.37-1.31 (m, 2H ), 0.90-0.85 (m, 2H).

LC-MS: m / z 282.9 [M + H] ⁺ at 1.85 RT (90.42% purity).

[Preparation Int-3]

( E ) -5- (1-Cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxaldehyde

Under an inert atmosphere, 5- (1-cyclopropyl-6-fluoro-1 H -benzo [d] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-2 (100 mg, 0.35 A stirred solution of mmol) in ethanol (EtOH) (2 mL) was added hydroxylamine hydrochloride (49 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol). The reaction mixture was heated to 80 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40 mL) and stirred for 10 min. The precipitated solid was filtered, washed with water (10 mL) and dried under vacuum to give ( E ) -5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazole-2- as an off-white solid. Propyl) pyrazine-3-carbaldehyde oxime (70 mg, 0.23 mmol, 67%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 12.25 (s, 1H), 9.81 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.80 (dd, J = 8.7,4.9 Hz, 1H), 7.55 (dd, J = 9.0, 1.7 Hz, 1H), 7.20 (td, J = 9.8, 2.3 Hz, 1H), 3.95-3.89 (m, 1H), 1.20-1.16 (m, 2H) , 0.84-0.79 (m, 2H).

LC-MS: m / z 297.9 [M + H] ⁺ at 1.95 RT (99.11% purity).

(5- (1-Cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methylamine (Int-3)

( E ) -5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde (70 mg) at room temperature under an inert atmosphere , 0.23 mmol) in a stirred solution of ethanol (5 mL) was added 10% Pd / C (50% wet, 25 mg). The reaction mixture was vented and stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through diatomaceous earth pad and washed with MeOH / CH ₂ Cl _2: washing (10 1,20mL). The filtrate was concentrated under reduced pressure to obtain (5- (1-cyclopropyl-6-fluoro-1H-benzo [d] imidazol-2-yl) pyrazin-3-yl) methylamine Int as an off-white solid. -3 (50 mg, crude), which was used in the next step without further purification.

LC-MS: m / z 283.9 [M + H] ⁺ at 1.62 RT (64.40% purity).

[Preparation Int-4]

3- (ethylamino) -4-nitrobenzonitrile

To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.05 mmol) in CH ₂ Cl ₂ (250 mL) under inert atmosphere, potassium carbonate (3.32 g, 24.09 mmol) and ethyl acetate were added at room temperature. Amine (70% aqueous solution, 2.17 g, 48.19 mmol). The reaction mixture was stirred at room temperature for 6 h. After consuming the starting material (by TLC), the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 3- (ethylamino) -4-nitrobenzonitrile (1.9 g, crude material) as a yellow solid, which required no further Purified and used in the next step.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.22-8.10 (m, 2H), 7.58 (br s, 1H), 7.00 (br d, J = 8.7Hz, 1H), 3.48-3.38 (m, 2H ), 1.21 (br t, J = 6.9Hz, 3H).

LC-MS: m / z 192.1 [M + H] ⁺ at 4.10 RT (98.96% purity).

4-Amino-3- (ethylamino) benzonitrile (Int-4)

To a stirred solution of 3- (ethylamino) -4-nitrobenzonitrile (1.9 g, crude material) in ethanol (20 mL), add 10% Pd / C (50%) at room temperature under an inert atmosphere. Wet, 190 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (50 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3- (ethylamino) benzonitrile Int-4 (1.5 g, crude) as an off-white solid, which was used in the next step without further purification. .

LC-MS: m / z 161.9 [M + H] ⁺ at 2.11 RT (60.88% purity).

[Preparation Int-5]

N -cyclopropyl-4,5-difluoro-2-nitroaniline

Under an inert atmosphere, potassium carbonate (390 mg, 2.82) was added dropwise to potassium 1,2,4-trifluoro-5-nitrobenzene (500 mg, 2.82 mmol) in potassium fluoride (164 mg, 2.82 mmol) at 0 ° C. mmol) and cyclopropylamine (0.23 mL, 3.39 mmol). The reaction mixture was stirred at 0 ° C for 30 min. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N -cyclopropyl-4,5-difluoro-2-nitroaminebenzene 2 (320 mg, crude material) as a pale yellow solid. , Which was used in the next step without further purification.

LC-MS: m / z 215.4 [M + H] ⁺ at 4.43 RT (69.03% purity).

N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine (Int-5)

To a stirred solution of N -cyclopropyl-4,5-difluoro-2-nitroaniline (300 mg, 1.4 mmol) in EtOAc (10 mL) was added 10% Pd / C (50 % Wet, 30 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (15 mL) and EtOAc (10 mL). The filtrate was concentrated under reduced pressure to obtain N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (100 mg, crude material) as a brown viscous slurry, which required no further purification Instead, use it for the next step.

LC-MS: m / z 184.9 [M + H] ⁺ at 2.12 RT (83.53% purity).

[Preparation of Int-6 & Int-7]

3- (cyclopropylamino) -4-nitrobenzonitrile

To a stirred solution of 3-fluoro-4-nitrobenzonitrile (1 g, 6.02 mmol) in CH ₂ Cl ₂ (5 mL) was added dropwise potassium carbonate (1.66 g, 12.05 mmol) at room temperature under an inert atmosphere. And cyclopropylamine (3.33 mL, 48.19 mmol). The reaction mixture was stirred at room temperature for 4 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 3- (cyclopropylamino) -4-nitrobenzonitrile (900 mg, crude material) as a yellow solid, which required no further Purified and used in the next step.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.24 (d, J = 8.7Hz, 1H), 8.07 (br s, 1H), 7.64 (d, J = 1.7Hz, 1H), 6.93 (dd, J = 8.7 , 1.7Hz, 1H), 2.62-2.57 (m, 1H), 1.03-0.97 (m, 2H), 0.72-0.67 (m, 2H).

LC-MS: m / z 201.9 [MH] ⁺ at 3.25 RT (99.61% purity).

4-amino-3- (cyclopropylamino) benzonitrile (Int-6)

To a stirred solution of 3- (cyclopropylamino) -4-nitrobenzonitrile (900 mg, 4.43 mmol) in ethanol (10 mL), add 10% Pd / C (50%) at room temperature under an inert atmosphere. Wet, 500 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 4-amino-3- (cyclopropylamino) benzonitrile Int-6 as an off-white solid. (500 mg, 2.89 mmol, 65%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 6.93 (d, J = 1.9Hz, 1H), 6.87 (dd, J = 8.0,1.9Hz, 1H), 6.55 (d, J = 8.0Hz, 1H) , 5.49 (s, 2H), 5.43 (s, 1H), 2.40-2.34 (m, 1H), 0.77-0.71 (m, 2H), 0.42-0.37 (m, 2H).

1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Int-7)

A solution of 4-amino-3- (cyclopropylamino) benzonitrile Int-6 (500 mg, 2.89 mmol) in formic acid (5 mL) was heated to reflux temperature under an inert atmosphere and stirred for 5 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (10 mL), neutralized with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile as an off-white solid. Int-7 (250 mg, 1.37 mmol, 56%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.50 (s, 1H), 8.21 (d, J = 0.9Hz, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.62 (dd, J = 8.4, 1.4Hz, 1H), 3.59-3.54 (m, 1H), 1.15-1.05 (m, 4H).

LC-MS: m / z 184.0 [M + H] ⁺ at 2.46 RT (87.33% purity).

[Preparation Int-8]

[Program]

6-chloro- N -cyclopropyl-3-nitropyridine-2-amine

Under a inert atmosphere, a stirred solution of 2,6-dichloro-3-nitropyridine (5 g, 26.04 mmol) in toluene (25 mL) was added cyclopropylamine (3.7 mL, 52.08 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 6-chloro- N -cyclopropyl-3-nitropyridine-2-amine as a pale yellow solid. (4 g, 18.77 mmol, 72%).

¹ H NMR (500MHz, CDCl ₃ ): δ 8.34 (d, J = 8.7Hz, 2H), 6.66 (d, J = 8.7Hz, 1H), 3.10-3.05 (m, 1H), 0.97-0.93 (m, 2H), 0.67-0.64 (m, 2H)

6-chloro- N 2-cyclopropylpyridine-2,3-diamine (Int-8)

To a stirred solution of 6-chloro- N -cyclopropyl-3-nitropyridine-2-amine (1 g, 4.69 mmol) in EtOH: water (1: 1, 10 mL) at room temperature under an inert atmosphere. Iron (1.3 g, 23.47 mmol) and ammonium chloride (1.2 g, 23.47 mmol) were added. The reaction mixture was heated to 80 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 6-chloro- N2 -cyclopropylpyridine-2,3-diamine Int as a pale yellow solid -8 (700 mg, crude), which was used in the next step without further purification.

LC-MS: m / z 183.9 [M + H] ⁺ at 2.07 RT (58.13% purity).

[Preparation Int-9]

N -cyclopropyl-6-methoxy-3-nitropyridine-2-amine

Under a inert atmosphere, a stirred solution of 2-chloro-6-methoxy-3-nitropyridine (5g, 26.5mmol) in toluene (50mL) was added at 0 ° C to cyclopropylamine (3.69mL, 53mmol ). The reaction mixture was stirred at 0 ° C for 1 h and warmed to room temperature and stirred for 6 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was triturated with n-pentane to give N -cyclopropyl-6-methoxy-3-nitropyridine-2-amine (800 mg, 3.82 mmol, 83%) as a yellow solid.

N ² -cyclopropyl-6-methoxypyridine-2,3-diamine (Int-9)

Iron powder was added to a stirred solution of N -cyclopropyl-6-methoxy-3-nitropyridine-2-amine (1 g, 4.78 mmol) in ethanol / water (1: 1, 10 mL) at room temperature. (1.3 g, 24 mmol) and ammonium chloride (1.29 g, 23.9 mmol). The reaction mixture was heated to 80 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to obtain N ² -cyclopropyl-6-methoxypyridine-2,3-diamine Int-9 (150 mg) as a black liquid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, DMSO- d ₆ ): δ 6.71 (d, J = 7.9Hz, 1H), 5.78 (d, J = 7.9Hz, 1H), 4.09-4.06 (m, 2H), 3.84-3.81 ( m, 1H), 3.70 (s, 3H), 2.77-2.68 (m, 1H), 0.69-0.61 (m, 2H), 0.43-0.37 (m, 2H)

LC-MS: m / z 180.1 [M + H] ⁺ at 2.11 RT (75.36% purity)

[Preparation Int-10]

N -ethyl-4,5-difluoro-2-nitroaniline

To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (2 g, 11.29 mmol) in CH ₂ Cl ₂ (10 mL) at room temperature was added potassium carbonate (3.1 g, 22.59 mmol) and ethylamine. (559 mg, 12.42 mmol). The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (100 mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 100mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to obtain N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 as a yellow solid). mmol, 35%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 8.19 (brs, 1H), 8.13 (dd, J = 11.0, 8.7Hz, 1H), 7.14 (dd, J = 13.9, 7.0Hz, 1H), 3.40- 3.33 (m, 2H), 1.20 (t, J = 7.2Hz, 3H)

LC-MS: m / z 203.1 [M + H] ⁺ at 3.53 RT (98.40% purity)

N ¹ -ethyl-4,5-difluorobenzene-1,2-diamine (Int-10)

To a stirred solution of N -ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol) in ethyl acetate (5 mL) was added 10% Pd / C ( 50% wet, 500 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to obtain N ¹ -ethyl-4,5-difluorobenzene-1,2-diamine Int-10 (500 mg, 2.90 mmol, 73%) as a black liquid, which required no further purification. Instead, use it for the next step.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.47 (dd, J = 12.8, 8.1Hz, 1H), 6.30 (dd, J = 13.3, 8.1Hz, 1H), 4.64 (br s, 2H), 4.44 (t, J = 5.2Hz, 1H), 3.00-2.94 (m, 2H), 1.17 (t, J = 7.2Hz, 3H)

LC-MS: m / z 173.2 [M + H] ⁺ at 3.16 RT (64.65% purity)

[Preparation Int-11]

6-chloro- N -ethyl-3-nitropyridine-2-amine

To a stirred solution of 2,6-dichloro-3-nitropyridine (2 g, 10.40 mmol) in toluene (8.5 mL) was added ethylamine (1.35 mL) at 0 ° C under an inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to give 6-chloro- N -ethyl-3-nitropyridine-2-amine (800 mg as a yellow solid) , 3.98 mmol, 38%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.70 (brs, 1H), 8.40 (d, J = 7.5Hz, 1H), 6.75 (d, J = 8.1Hz, 1H), 3.55-3.50 (m, 2H), 1.18 (t, J = 7.0Hz, 3H)

LC-MS: m / z 202 [M + H] ⁺ at 2.63 RT (99.85% purity)

6-chloro- N ² -ethylpyridine-2,3-diamine (Int-11)

To a stirred solution of 6-chloro- N -ethyl-3-nitropyridine-2-amine (550 mg, 2.73 mmol) in ethanol / water (1: 1, 20 mL) was added iron powder (763.4 g) at room temperature. , 13.68 mmol) and ammonium chloride (738.7 mg, 13.68 mmol). The reaction mixture was heated to 80 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 6-chloro- N ² -ethylpyridine -2,3-diamine Int- as a black solid 11 (452mg). The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.67 (d, J = 7.5Hz, 1H), 6.33 (d, J = 8.1Hz, 1H), 5.85 (brs, 1H), 4.88 (br s, 2H ), 3.37-3.25 (m, 2H), 1.15 (t, J = 7.0Hz, 3H)

LC-MS: m / z 172 [M + H] ⁺ at 1.72 RT (85.88% purity)

[Preparation Int-12]

[Program]

4,5-difluoro-2-nitrosamine

To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.24 mmol) in methanol (5 mL) was added methanolic ammonia (15 mL) at 0 ° C under an inert atmosphere. The reaction mixture was heated to 90 ° C and stirred in a sealed tube for 2 h. After consuming the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to obtain 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol, 16%) as a pale yellow solid. ).

¹ H NMR (500MHz, CDCl ₃ ) : δ 8.00 (dd, J = 10.4,8.7Hz, 1H), 6.60 (dd, J = 11.0,6.4Hz, 1H), 6.09 (brs, 2H)

LC-MS: m / z 172.8 [MH] - in 2.49 RT (88.25% purity)

4,5-difluorobenzene-1,2-diamine (Int-12)

To a stirred solution of 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol) in methanol (15 mL) was added 10% Pd / C (50% wet, 200 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (15 mL) and CH ₂ Cl ₂ (10 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-hexane (15 mL) to obtain 4,5-difluorobenzene-1,2-diamine Int-12 (500 mg, 3.47 mmol, 80%) as a black solid.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 6.47-6.41 (m, 2H), 4.55 (brs, 4H)

LC-MS: m / z 145 [M + H] ⁺ at 1.59 RT (75.16% purity)

[Preparation Int-13]

5-chloro- N -cyclopropyl-3-nitropyridine-2-amine

To a stirred solution of 2,5-dichloro-3-nitropyridine (1 g, 5.23 mmol) in toluene (10 mL) was added cyclopropylamine (0.73 mL, 10.47 mmol) at 0 ° C under an inert atmosphere. The reaction mixture was stirred at room temperature for 48 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 5-chloro- N -cyclopropyl-3-nitropyridine-2-amine (700 mg, 3.28 mmol, 63 %).

¹ H NMR (400MHz, CDCl ₃ ) : δ 8.45 (d, J = 2.5Hz, 1H), 8.41 (d, J = 2.4Hz, 1H), 8.18 (br s, 1H), 3.05-2.97 (m, 1H ), 0.98-0.91 (m, 2H), 0.68-0.62 (m, 2H)

LC-MS: m / z 214 [M + H] ⁺ at 3.03 RT (98.66% purity)

5-chloro- N ² -cyclopropylpyridine-2,3-diamine (Int-13)

To a stirred solution of 5-chloro- N -cyclopropyl-3-nitropyridine-2-amine (200 mg, 0.938 mmol) in ethanol / water (1: 1, 20 mL) at room temperature was added iron powder (262 mg , 4.69 mmol) and ammonium chloride (253 mg, 4.69 mmol). The reaction mixture was heated to 80 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 5-chloro- N ² -cyclopropylpyridine-2,3-diamine Int-13 (120 mg) as a black solid. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 7.35 (d, J = 1.7Hz, 1H), 6.67 (d, J = 2.3Hz, 1H), 6.00 (br s, 1H), 5.02 (br s, 2H), 2.72-2.63 (m, 1H), 0.68-0.63 (m, 2H), 0.41-0.37 (m, 2H)

LC-MS: m / z 183.9 [M + H] ⁺ at 1.87 RT (88.05% purity)

[Preparation Int-14]

[Program]

N -cyclopropyl-2-fluoro-6-nitroaniline

To a stirred solution of 1,2-difluoro-3-nitrobenzene (200 mg, 1.26 mmol) in ethanol (2 mL) at room temperature, cyclopropylamine (0.13 mL, 1.89 mmol) was added and stirred for 16 h . After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to obtain N -cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02) as a yellow viscous slurry. mmol, 81%).

¹ H NMR (400MHz, CDCl ₃ ): δ 7.93 (dt, J = 8.8, 1.5Hz, 1H), 7.82 (brs, 1H), 7.24-7.19 (m, 1H), 6.63-6.58 (m, 1H), 3.12-3.07 (m, 1H), 0.87-0.79 (m, 2H), 0.67-0.61 (m, 2H)

LC-MS: m / z 197.0 [M + H] ⁺ at 3.28 RT (99.89% purity)

N ¹ -cyclopropyl-6-fluorobenzene-1,2-diamine (Int-14)

To a stirred solution of N -cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol) in ethyl acetate (5 mL) at room temperature, 10% Pd / C (50% Wet, 30 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to give N ¹ -cyclopropyl-6-fluorobenzene-1,2-diamine Int-14 (160 mg) as a colorless viscous slurry. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.61-6.51 (m, 1H), 6.40-6.24 (m, 3H), 4.89 (br s, 2H), 2.62-2.58 (m, 1H), 0.49- 0.38 (m, 4H)

[Preparation Int-15]

4,5-difluoro- N -methyl-2-nitroamine

To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (50 mL) at -20 ° C, methylamine (2M in THF) was added dropwise. , 28.25 mL, 56.5 mmol), and allowed to stir at the same temperature for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with brine (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to obtain 4,5-difluoro- N -methyl-2-nitroaniline (1.1 g) as a pale yellow solid. , 5.85 mmol, 20%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.06 (dd, J = 10.7,8.4Hz, 2H), 6.61 (dd, J = 12.5, 6.7Hz, 1H), 3.01 (d, J = 5.1Hz, 3H)

4,5-difluoro- N ¹ -methylbenzene-1,2-diamine (Int-15)

To a stirred solution of 4,5-difluoro- N -methyl-2-nitroaniline (1 g, 5.32 mmol) in ethyl acetate (15 mL) was added 10% Pd / C ( 50% wet, 250 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to obtain 4,5-difluoro- N ¹ -methylbenzene-1,2-diamine Int-15 (700 mg) as a brown slurry. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.48 (dd, J = 12.5, 8.4Hz, 1H), 6.28 (dd, J = 13.3, 8.1Hz, 1H), 4.71 (s, 1H), 4.59 ( br s, 2H), 2.66 (d, J = 5.2Hz, 3H)

LC-MS: m / z 158.8 [M + H] ⁺ at 2.20 RT (99.55% purity)

[Preparation Int-16]

4,5-difluoro-2-nitro- N -propylaniline

To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (150 mL) at room temperature, potassium carbonate (5.07 g, 36.72 mmol) was added dropwise. ) And propan-1-amine (3.48 mL, 42.37 mmol) and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to obtain 4,5-difluoro-2-nitro- N -propylaniline (600 mg, 2.77 as a yellow solid). mmol, 10%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.25 (br s, 1H), 8.14 (dd, J = 11.3, 8.7Hz, 1H), 7.17 (dd, J = 13.7, 7.2Hz, 1H), 3.35 -3.26 (m, 2H), 1.68-1.56 (m, 2H), 0.93 (t, J = 7.4Hz, 3H)

4,5-difluoro- N ¹ -propylbenzene-1,2-diamine (Int-16)

To a stirred solution of 4,5-difluoro-2-nitro- N -propylaniline (500 mg, 2.31 mmol) in ethyl acetate (10 mL) was added 10% Pd / C ( 50% wet, 150 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to obtain 4,5-difluoro- N ¹ -propylbenzene-1,2-diamine Int-16 (350 mg) as a brown slurry. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.48 (dd, J = 12.8, 8.1Hz, 1H), 6.30 (dd, J = 13.3, 8.1Hz, 1H), 4.66 (s, 2H), 4.47 ( br t, J = 4.6Hz, 1H), 2.96-2.88 (m, 2H), 1.62-1.54 (m, 2H), 0.95 (t, J = 7.5Hz, 3H)

LC-MS: m / z 186.9 [M + H] ⁺ at 2.88 RT (89.94% purity)

[Preparation Int-17]

3- (cyclopropylamino) -4-nitrophenol

To a stirred solution of 3-fluoro-4-nitrophenol (1 g, 6.37 mmol) in THF (20 mL) was added cyclopropylamine (726 mg, 12.74 mmol) in a sealed tube at room temperature under an inert atmosphere. The reaction mixture was heated to 80 ° C and stirred for 6 h. After consuming the starting material (by TLC), the reaction mixture was poured into ice-cold water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 3- (cyclopropylamino) -4-nitrophenol (1.2 g, 6.18 as a yellow solid). mmol, 75%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.86 (br s, 1H), 8.15 (br s, 1H), 7.97 (d, J = 9.3Hz, 1H), 6.61 (d, J = 1.7Hz, 1H), 6.22 (dd, J = 9.3, 2.3Hz, 1H), 2.57-2.55 (m, 1H), 0.91-0.82 (m, 2H), 0.67-0.57 (m, 2H)

LC-MS: m / z 194.9 [M + H] ⁺ at 2.51 RT (99.35% purity)

4-Amino-3- (cyclopropylamino) phenol (Int-17)

To a stirred solution of 3- (cyclopropylamino) -4-nitrophenol (1 g, 5.15 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50 % Wet, 250 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3- (cyclopropylamino) phenol Int-17 (600 mg) as a brown slurry. The crude material was used in the next step without further purification.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 8.18 (brs, 1H), 6.37-6.29 (m, 2H), 5.86 (dd, J = 8.1, 2.3 Hz, 1H), 4.92 (s, 1H), 3.81 (brs, 2H), 2.27-2.25 (m, 1H), 0.69-0.62 (m, 2H), 0.41-0.35 (m, 2H)

LC-MS: m / z 164.8 [M + H] ⁺ at 1.09 RT (74.22% purity)

[Preparation Int-18]

N -cyclopropyl-5-methyl-2-nitrosamine

To a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in THF (5 mL) at room temperature, triethylamine (1.35 mL, 9.68 mmol) was added. Followed by cyclopropylamine (919 mg, 16.13 mmol). The reaction mixture was heated to 60 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N -cyclopropyl-5-methyl-2-nitroaniline (500 mg, 2.6 mmol) as a yellow solid. , 80%).

¹ H NMR (500MHz, CDCl ₃ ): δ 8.10 (brs, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.07 (s, 1H), 6.50 (d, J = 8.8Hz, 1H), 2.58 -2.55 (m, 1H), 2.37 (s, 3H), 0.94-0.88 (m, 2H), 0.67-0.62 (m, 2H).

LC-MS: m / z 192.9 [M + H] ⁺ at 3.35 RT (99.53% purity).

N ¹ -cyclopropyl-5-methylbenzene-1,2-diamine (Int-18)

To a stirred solution of N -cyclopropyl-5-methyl-2-nitroaniline (150 mg, 0.78 mmol) in ethyl acetate (1 mL) at room temperature, 10% Pd / C (50 % Wet, 50 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to give N ¹ -cyclopropyl-5-methylbenzene-1,2-diamine Int-18 (120 mg) as a black solid. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.60 (s, 1H), 6.41 (d, J = 8.1Hz, 1H), 6.24 (br d, J = 7.5Hz, 1H), 4.91 (s, 1H ), 4.21 (br s, 2H), 2.32-2.30 (m, 1H), 2.14 (s, 3H), 0.71-0.64 (m, 2H), 0.41-0.35 (m, 2H)

LC-MS: m / z 162.9 [M + H] ⁺ at 2.49 RT (81.92% purity)

[Preparation Int-19]

N -cyclopropyl-2-nitro-5- (trifluoromethyl) aniline

To a stirred solution of 2-fluoro-1-nitro-4- (trifluoromethyl) benzene (1 g, 4.78 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ° C was added potassium carbonate ( 1.32 g, 9.57 mmol) and cyclopropylamine (1.09 g, 19.14 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with CH ₂ Cl ₂ (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N -cyclopropyl-2-nitro-5- (trifluoromethyl) aniline as a yellow solid. (1 g, 4.06 mmol, 85%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.25 (d, J = 8.9Hz, 1H), 8.13 (brs, 1H), 7.62 (d, J = 1.0Hz, 1H), 7.04 (dd, J = 8.8, 1.8Hz, 1H), 2.76-2.69 (m, 1H), 0.95-0.87 (m, 2H), 0.69-0.63 (m, 2H)

LC-MS: m / z 245.0 [MH] - in 4.33 RT (78.90% purity)

N ¹ -cyclopropyl-5- (trifluoromethyl) benzene-1,2-diamine (Int-19)

To a stirred solution of N -cyclopropyl-2-nitro-5- (trifluoromethyl) aniline (1 g, 4.06 mmol) in methanol (20 mL) was added 10% Pd / at room temperature under an inert atmosphere. C (50% wet, 100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give N ¹ -cyclopropyl-5- (trifluoromethyl) benzene-1,2-diamine Int-19 (700 mg) as a brown slurry. The crude material was used in the next step without further purification.

[Preparation Int-20]

N -cyclopropyl-2,3-difluoro-6-nitroaniline

To a stirred solution of 1,2,3-trifluoro-4-nitrobenzene (1 g, 28.25 mmol) in ethanol (100 mL) at room temperature was added cyclopropylamine (1.61 g, 28.25 mmol) and The reaction was stirred for 48 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to obtain N -cyclopropyl-2,3-difluoro-6-nitroaniline (3g, 14.0 mmol, 50%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 7.95-7.91 (m, 1H), 7.75 (brs, 1H), 6.85-6.80 (m, 1H), 3.02-2.98 (m, 1H), 0.79-0.72 (m, 2H), 0.67-0.65 (m, 2H)

LC-MS: m / z 213.4 [MH] ⁺ at 4.06 RT (99.81% purity)

N ¹ -cyclopropyl-5,6-difluorobenzene-1,2-diamine (Int-20)

To a stirred solution of N -cyclopropyl-2,3-difluoro-6-nitroaniline (1 g, 4.67 mmol) in ethyl acetate (10 mL) was added 10% Pd / C at room temperature under an inert atmosphere. (50% wet, 100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 2 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to obtain N ¹ -cyclopropyl-5,6-difluorobenzene-1,2-diamine Int-20 (700 mg) as a black solid. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.55-6.47 (m, 1H), 6.33-6.27 (m, 1H), 4.70 (br s, 2H), 4.54 (br s, 1H), 2.74-2.66 (m, 1H), 0.59-0.52 (m, 2H), 0.48-0.43 (m, 2H)

LC-MS: m / z 185.0 [M + H] ⁺ at 2.60 RT (67.33% purity)

[Preparation Int-21]

N -cyclobutyl-4,5-difluoro-2-nitroaniline

To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.65 mmol) in THF (20 mL) at 0 ° C was added potassium carbonate (1.17 g, 8.47 mmol), Cyclobutylamine (0.58 mL, 6.78 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 6 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to obtain N -cyclobutyl-4,5-difluoro-2-nitroaniline (450 mg, 1.97 mmol, 35%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 8.18-8.08 (m, 2H), 7.00 (dd, J = 13.4, 7.0Hz, 1H), 4.16-4.07 (m, 1H), 2.48-2.39 (m , 2H), 2.06-1.94 (m, 2H), 1.83-1.69 (m, 2H)

LC-MS: m / z 229.0 [M + H] ⁺ at 2.90 RT (97.77% purity)

N ¹ -cyclobutyl-4,5-difluorobenzene-1,2-diamine (Int-21)

To a stirred solution of N-cyclobutyl-4,5-difluoro-2-nitroaniline (450 mg, 1.97 mmol) in ethyl acetate (10 mL) was added 10% Pd / C at room temperature under an inert atmosphere. (50% wet, 45mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to obtain N ¹ -cyclobutyl-4,5-difluorobenzene-1,2-diamine Int-21 (350 mg) as a black solid. This crude material was used in the next step without further purification.

¹ H NMR (500MHz, CDCl ₃ ): δ 6.52 (dd, J = 11.3, 8.0Hz, 1H), 6.33 (dd, J = 12.1, 7.1Hz, 1H), 3.86-3.76 (m, 1H), 3.40- 3.18 (m, 3H), 2.52-2.39 (m, 2H), 1.91-1.78 (m, 4H)

LC-MS: m / z 199.0 [M + H] ⁺ at 2.92 RT (83.44% purity)

[Preparation Int-22]

4- (cyclopropylamino) -3-nitrobenzonitrile

To a stirred solution of 4-fluoro-3-nitrobenzonitrile (1 g, 6.02 mmol) in CH ₂ Cl ₂ (5 mL) at 0 ° C was added potassium carbonate (1.66 g, 12.05 mmol) dropwise. Followed by cyclopropylamine (3.33 mL, 48.19 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 4- (cyclopropylamino) -3-nitrobenzonitrile (1.1 g) as a yellow solid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.49 (d, J = 1.9Hz, 1H), 8.41 (brs, 1H), 7.66-7.63 (m, 1H), 7.40 (d, J = 9.0Hz, 1H) , 2.68-2.61 (m, 1H), 1.04-0.98 (m, 2H), 0.75-0.70 (m, 2H)

LC-MS: m / z 202.0 [MH] - in 2.88 RT (99.48% purity)

3-Amino-4- (cyclopropylamino) benzonitrile (Int-22)

To a stirred solution of 4- (cyclopropylamino) -3-nitrobenzonitrile (1.1 g, crude material) in ethanol (40 mL) at room temperature, 1.10% Pd / C (50 % Wet, 350 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to obtain 3-amino-4- (cyclopropylamino) benzonitrile Int-22 (900 mg) as a yellow solid liquid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.18 (dd, J = 8.2, 1.8Hz, 1H), 7.00 (d, J = 8.3Hz, 1H), 6.92 (d, J = 1.9Hz, 1H), 4.41 (br s, 1H), 3.24 (br s, 2H), 2.51-2.43 (m, 1H), 0.85-0.78 (m, 2H), 0.59-0.53 (m, 2H)

LC-MS: m / z 173.9 [M + H] ⁺ at 2.40 RT (84.82% purity)

[Preparation Int-23]

1-chloro-2,5-difluoro-4-nitrobenzene

To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (500 mg, 2.59 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C under an inert atmosphere was added potassium carbonate (715 mg, 5.18 mmol) and cyclopropylamine (305 mg, 5.18 mmol). The reaction mixture was stirred at room temperature for 24 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.73 mmol, 67%) as a yellow solid.

¹ H NMR (500MHz, CDCl ₃ ): δ 7.97 (d, J = 9.3Hz, 2H), 7.37 (d, J = 6.4Hz, 1H), 2.57-2.54 (m, 1H), 1.00-0.91 (m, 2H), 0.71-0.59 (m, 2H)

5-chloro- N ¹ -cyclopropyl-4-fluorobenzene-1,2-diamine (Int-23)

To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.74 mmol) in EtOAc (10 mL) was added 10% Pd / C (50%) at room temperature under an inert atmosphere. Wet, 100 mg). The reaction mixture was vented and stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to obtain 5-chloro- N ¹ -cyclopropyl-4-fluorobenzene-1,2-diamine Int-23 (280 mg, 1.40 mmol, 81%) as an off-white solid.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.68 (d, J = 7.5Hz, 1H), 6.47 (d, J = 11.6Hz, 1H), 5.16 (br s, 1H), 4.96 (br s, 2H), 2.34-2.27 (m, 1H), 0.74-0.67 (m, 2H), 0.42-0.28 (m, 2H)

[Preparation Int-24]

4-chloro- N -cyclopropyl-2-nitroaniline

To 4-chloro-1-fluoro-2-nitrobenzene (2 g, 11.43 mmol) was added dropwise cyclopropylamine (2.6 g, 45.71 mmol) under an inert atmosphere at 10 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3-5% EtOAc / hexane) to give 4-chloro- N -cyclopropyl-2-nitroaniline (2.08 g, 0.98 mmol, 83%).

¹ H NMR (500MHz, CDCl ₃ ): δ 8.16 (d, J = 2.2Hz, 1H), 8.04 (br s, 1H), 7.42 (dd, J = 8.8,2.2Hz, 1H), 7.29 (d, J = 9.3Hz, 1H), 2.61-2.55 (m, 1H), 0.96-0.90 (m, 2H), 0.69-0.63 (m, 2H)

LC-MS: m / z 213.1 [M + H] ⁺ at 2.85 RT (99.81% purity)

4-Chloro- N ¹ -cyclopropylbenzene-1,2-diamine (Int-24)

To a stirred solution of 4-chloro- N -cyclopropyl-2-nitroaniline (1 g, 4.72 mmol) in methanol ammonia (2M, 50 mL) at room temperature was added Raleigh nickel (500 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give 4-chloro- N ¹ -cyclopropylbenzene-1,2-diamine Int-24 (700 mg) as a brown liquid. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 6.70 (d, J = 8.3Hz, 1H), 6.55-6.45 (m, 2H), 5.10 (s, 1H), 4.77 (br s, 2H), 2.31 -2.29 (m, 1H), 0.72-0.65 (m, 2H), 0.41-0.34 (m, 2H)

LC-MS: m / z 183.1 [M + H] ⁺ at 2.15 RT (87.51% purity)

[Preparation Int-25]

3-chloro- N -cyclopropyl-2-nitroaniline

To 1-chloro-3-fluoro-2-nitrobenzene (500 mg, 2.85 mmol) was added dropwise cyclopropylamine (0.78 mL, 11.4 mmol) at room temperature under an inert atmosphere and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ dried and concentrated under reduced pressure to give a yellow solid 3-chloro -N- cyclopropyl-2-nitro aniline (500mg). The crude material was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28-7.22 (m, 1H), 7.15 (dd, J = 8.5, 1.3 Hz, 1H), 6.80 (dd, J = 7.8, 1.3 Hz, 1H), 6.01 ( br s, 1H), 2.54-2.46 (m, 1H), 0.88-0.82 (m, 2H), 0.60-0.55 (m, 2H).

LC-MS: m / z 213.1 [M + H] ⁺ at 2.74 RT (98.57% purity)

3-chloro- N ¹ -cyclopropylbenzene-1,2-diamine (Int-25)

To a stirred solution of 3-chloro- N -cyclopropyl-2-nitroaniline (200 mg, crude material) in acetic acid (2 mL) at room temperature, iron powder (157 mg, 2.83 mmol) was added. The reaction mixture was heated to 80 ° C and stirred for 1 h. After consumption of the starting material (by TLC), the reaction mixture (20mL) was quenched with saturated NaHCO ₃ solution and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 3-chloro- N ¹ -cyclopropylbenzene-1,2-diamine Int-25 (200 mg) as a brown slurry. The crude material was used in the next step without further purification.

LC-MS: m / z 183.0 [M + H] ⁺ at 2.47 RT (43.71% purity)

[Preparation Int-26]

4-isopropyl-2- (trifluoromethyl) oxazole-5 (2 H ) -one

To DL-valine acid (30 g, 256.41 mmol) was added trifluoroacetic anhydride (72 mL) dropwise at room temperature. The reaction mixture was heated to reflux and stirred for 8 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (250 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 4-isopropyl-2- (trifluoromethyl) oxazole-5 (2 H ) -one 2 as a pale yellow liquid. (45g). The crude material was used in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) : δ 6.11-6.05 (m, 1H), 3.12-3.02 (m, 1H), 1.34 (d, J = 3.0Hz, 3H), 1.32 (d, J = 3.0Hz, 3H)

LC-MS: m / z 193.9 [MH] - in 2.94 RT (75.69% purity)

Diethyl 2-((4-isopropyl-5- pendantoxy-2- (trifluoromethyl) -2,5-dihydroxyoxazol-2-yl) methyl) malonate

Under an inert atmosphere, 4-isopropyl-2- (trifluoromethyl) oxazole-5 (2 H ) -one (45 g, crude material) in CH ₂ Cl ₂ (450 mL) was added at 0 ° C. The stirred solution was added diethyl methylenemalonate (47.63 g, crude material) and triethylamine (48.2 mL, 346.14 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (150 mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 250mL} ). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 2-((4-isopropyl-5- pendantoxy-2- (trifluoromethyl)- 2,5-Dihydroxyoxazol-2-yl) methyl) diethylmalonate (50 g, crude). The crude material was used in the next step without further purification.

LC-MS: m / z 368.1 [M + H] ⁺ at 3.70 RT (82.98% purity)

3-Ethoxy-6- (trifluoromethyl) -2,3,4,5-tetrahydropyrazine-4-carboxylic acid ethyl ester

Under an inert atmosphere at room temperature toward 2-((4-isopropyl-5- pendantoxy-2- (trifluoromethyl) -2,5-dihydroxyoxazol-2-yl) methyl ) A stirred solution of diethyl malonate (25 g, crude material) in acetic acid (200 mL) was added hydrazine hydrochloride (23.16 g, 340.59 mmol). The reaction mixture was heated to reflux and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give 3-sideoxy-6- (trifluoromethyl) -2 as a pale yellow liquid, 3,4,5-Tetrahydropyrazine-4-carboxylic acid ethyl ester (15 g, 63.55 mmol).

LC-MS: m / z 237.0 [MH] - in 2.19 RT (87.20% purity)

3-hydroxy-6- (trifluoromethyl) pyrazine-4-carboxylic acid ethyl ester

Under an inert atmosphere, at the temperature of 0 ° C. to ethyl 3- pendantoxy-6- (trifluoromethyl) -2,3,4,5-tetrahydropyrazine-4-carboxylate (7.5 g, 31.51 mmol) To a stirred solution of acetic acid (40 mL) was added a solution of bromine (5.03 g, 31.51 mmol) in acetic acid (35 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give 3-hydroxy-6- (trifluoromethyl) pyrazine-4-carboxylic acid as an off-white solid. Ethyl ester (2.5 g, 10.59 mmol, 34%).

¹ H NMR (400 MHz, DMSO- d ₆ ) : δ 14.16 (br s, 1H), 8.12 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H )

LC-MS: m / z 235.0 [MH] - in 2.03 RT (98.67% purity)

3-chloro-6- (trifluoromethyl) pyridazine-4-carboxylic acid ethyl ester

Under an inert atmosphere, ethyl 3-hydroxy-6- (trifluoromethyl) pyrazine-4-carboxylate (5.0 g, 21.19 mmol) in 1,4-dioxane (50 mL) was added at 0 ° C. Stirring solution was added phosphonium trichloride (19.6 mL, 211.86 mmol). The reaction mixture was heated to 100 ° C and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 15-20% EtOAc / hexane) to give 3-chloro-6- (trifluoromethyl) pyrazine-4- as a pale yellow liquid. Ethyl formate (3 g, 11.81 mmol, 55%).

¹ H NMR (500MHz, CDCl ₃ ) : δ 8.15 (s, 1H), 4.53 (q, J = 7.0Hz, 2H), 1.47 (t, J = 7.2Hz, 3H)

LC-MS: m / z 255.4 [M + H] ⁺ at 3.61 RT (98.51% purity)

6- (trifluoromethyl) pyrazine-4-carboxylic acid ethyl ester

To a stirred solution of ethyl 3-chloro-6- (trifluoromethyl) pyrazine-4-carboxylate (500 mg, 1.96 mmol) in ethanol (10 mL) was added triethylamine ( 0.5 mL) and 10% Pd / C (50% wet, 100 mg). The reaction headspace was briefly placed under vacuum and quickly refilled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The obtained crude substance was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to obtain 6- (trifluoromethyl) pyrazine-4-carboxylic acid ethyl ester (off-white solid) 300 mg, 1.36 mmol, 69%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.85 (d, J = 1.8Hz, 1H), 8.32 (d, J = 1.9Hz, 1H), 4.53 (q, J = 7.2Hz, 2H), 1.47 (t , J = 7.2Hz, 3H)

LC-MS: m / z 221.1 [M + H] ⁺ at 3.09 RT (92.69% purity)

6- (trifluoromethyl) pyrazine-4-carboxylic acid (Int-26)

To a stirred solution of 6- (trifluoromethyl) pyrazine-4-carboxylic acid ethyl ester (300 mg, 1.36 mmol) in a mixture of THF: water (4: 1,5 mL) at 0 ° C was added lithium hydroxide (171.6 g, 4.09 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified using concentrated HCl (pH 3-4) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The obtained solid was washed with n-pentane (10 mL) and dried under vacuum to give 6- (trifluoromethyl) pyrazine-4-carboxylic acid Int-26 (210 mg) as an off-white solid. The crude material was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO- d ₆ ) : δ 14.08 (brs, 1H), 9.83 (brs, 1H), 8.43 (brs, 1H)

LC-MS: m / z 191.0 [MH] - in 3.79 RT (94.51% purity)

[Preparation Int-27]

1-cyclopropyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 150 mg, 0.50 mmol) in a stirred solution of 1,4-dioxane (3 mL) and water (0.5 mL), and vinyl borate pinacol ester (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol). The reaction mixture was degassed with argon for 10 min. Pd (dppf) Cl ₂ (4 mg, 0.005 mmol) was added at room temperature and the mixture was degassed with argon for 10 min. The reaction mixture was heated to 80 ° C and stirred for 5 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-vinyl) as an off-white solid. pyridazin-4-yl) -1 H - benzo [d] imidazole (70mg, 0.23mmol, 48%) .

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7Hz, 1H), 5.82 (d, J = 11.4Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde (Int-27)

Under an inert atmosphere, 1-cyclopropyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (300 mg, 1.00 mmol) in a stirred solution of acetone: ^t BuOH: water (1: 1: 1,18 mL) was added sodium periodate (430 mg, 2.01 mmol) and osmium tetraoxide (1 M solution, 6 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to give 5- (1-cyclopropyl-5,6-difluoro-1 H as a black solid. -Benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 (200 mg). The crude material was used without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.36 (s, 1H), 10.03 (s, 1H), 8.58 (s, 1H), 7.93-7.81 (m, 2H), 4.00-3.94 (m, 1H ), 1.21-1.13 (m, 2H), 0.81-0.72 (m, 2H)

[Preparation Int-28]

[Program]

( E ) -5- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxime

To 5- (1-cyclopropyl-5,6-difluoro-1H-benzo [d] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 (600mg , 2 mmol) in a stirred solution of ethanol (10 mL) was added hydroxylamine hydrochloride (276 mg, 4 mmol) and potassium carbonate (552 mg, 4 mmol). The reaction mixture was heated to 80 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with CH ₂ Cl ₂ (100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was washed with n-hexane (20 mL) and dried under vacuum to give ( E ) -5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazole-2 as an off-white solid. -Yl) pyridazin-3-carbaldehyde oxime (500 mg, 1.58 mmol, 79%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 12.26 (s, 1H), 9.80 (d, J = 1.7Hz, 1H), 8.56 (d, J = 2.3Hz, 1H), 8.48 (s, 1H) , 7.91-7.80 (m, 2H), 3.97-3.88 (m, 1H), 1.22-1.14 (m, 2H), 0.85-0.78 (m, 2H)

LC-MS: m / z 315.9 [M + H] ⁺ at 2.33 RT (97.99% purity)

(5- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazol-2-yl) pyrazin-3-yl) methylamine (Int-28)

To ( E ) -5- (1-cyclopropyl-56-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde oxime ( A stirred solution of 500 mg, 1.58 mmol) in ethanol (10 mL) was added sodium hydroxide (190 mg, 4.76 mmol) and 10% Pd / C (50% wet, 150 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (80 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole-2) as an off-white solid. -Yl) pyridazin-3-ylmethylamine Int-28 (400 mg, 1.32 mmol, 84%). The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.68 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 7.89-7.81 (m, 2H), 4.12 (s, 2H), 3.95-3.89 (m, 1H), 2.13 (brs, 2H), 1.27-1.14 (m, 2H), 0.79-0.66 (m, 2H)

LC-MS: m / z 301.9 [M + H] ⁺ at 1.91 RT (95.51% purity)

[Preparation Int-29]

[Program]

6- (Difluoromethyl) pyrazine-4-carboxylic acid (Int-29) is prepared in a similar manner to Int-26 starting with alanine and difluoroacetic anhydride (DFAA).

[Preparation Int-30]

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one oxime

To 1- (5- (1-cyclopropyl-5,6-difluoro-1H-benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl at 0 ° C under an inert atmosphere. To a stirred solution of 1-one Example 64 (170 mg, 0.54 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (75 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol). The reaction mixture was heated to 80 ° C and stirred for 3 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (2 x 40 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d] as an off-white solid. ] Imidazol-2-yl) pyridazin-3-yl) ethan-1-one oxime (100 mg). The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 12.07 (s, 1H), 9.81 (d, J = 1.7Hz, 1H), 8.63 (d, J = 1.7Hz, 1H), 7.91-7.80 (m, 2H), 3.94-3.87 (m, 1H), 2.41 (s, 3H), 1.21-1.14 (m, 2H), 0.85-0.76 (m, 2H)

LC-MS: m / z 329.9 [M + H] ⁺ at 2.52 RT (86.46% purity)

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethyl-1-amine (Int-30)

To 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at room temperature under an inert atmosphere To a stirred solution of aceto-1-ketoxime (100 mg, crude material) in ethanol (10 mL) was added sodium hydroxide (37 mg, 0.91 mmol) and 10% Pd / C (50% wet, 80 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 8 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d] as an off-white solid. ] Imidazol-2-yl) pyridazin-3-yl) ethyl-1-amine Int-30 (80 mg). The crude material was used without further purification.

LC-MS: m / z 315.9 [M + H] ⁺ at 1.71 RT (85.70% purity)

[Example 1]

N- (2- (cyclopropylamino) -4-fluorophenyl) pyrazine-4-carboxamide

N 1 -cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (300 mg, 1.81 mmol) in N, N -dimethylformamide ( N , N -dimethylformamide; DMF) (3mL) was added to a stirred solution of pyridazine-4-carboxylic acid (224mg, 1.81mmol), N -[(dimethylamino) -1 H -1,2,3-triazole Benzo [4,5- b ] pyridin-1-ylmethylene] -N -methylmethylamineium hexafluorophosphate N -oxide (HATU) (824mg, 2.17mmol) and ethyldiisopropylamine (1.26 mL, 7.23 mmol). The reaction mixture was stirred at room temperature for 8 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give N- (2- (cyclopropylamino) -4-fluorophenyl) DA as a brown solid. Azine-4-methylamidine (220 mg, 0.81 mmol, 44%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.89 (s, 1H), 9.66 (dd, J = 2.2, 1.3Hz, 1H), 9.47 (dd, J = 5.2, 1.1Hz, 1H), 8.12 ( dd, J = 5.3, 2.3Hz, 1H), 7.13 (dd, J = 8,5,6.4Hz, 1H), 6.75 (dd, J = 11.9,2.9Hz, 1H), 6.43 (td, J = 8.5, 2.9Hz, 1H), 6.12 (s, 1H), 2.38-2.32 (m, 1H), 0.77-0.71 (m, 2H), 0.47-0.40 (m, 2H).

LC-MS: m / z 272.9 [M + H] ⁺ at 2.66 RT (89.14% purity).

1-cyclopropyl-6-fluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (Ex 1)

Under inert atmosphere, heat N- (2- (cyclopropylamino) -4-fluorophenyl) pyrazine-4-carboxamide (150 mg, 0.55 mmol) in acetic acid (3 mL) to 100 ° C and stir for 8 h . After consuming the starting material (by TLC), the reaction mixture was neutralized with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-6-fluoro-2- (dazin-4- ) -1H-benzo [ d ] imidazole Ex 1 (68 mg, 0.27 mmol, 48%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.82 (dd, J = 2.2,1.3Hz, 1H), 9.45 (dd, J = 5.4,1.1Hz, 1H), 8.29 (dd, J = 5.4,2.4 Hz, 1H), 7.79 (dd, J = 8.9, 4.9 Hz, 1H), 7.55 (dd, J = 9.1, 2.4 Hz, 1H), 7.22-7.15 (m, 1H), 3.94-3.87 (m, 1H) , 1.22-1.16 (m, 2H), 0.78-0.73 (m, 2H).

LC-MS: m / z 255.0 [M + H] ⁺ at 2.98 RT (97.13% purity).

HPLC: 98.24%.

[Example 2 & 3]

6-chloro- N- (2- (cyclopropylamino) -4-fluorophenyl) pyrazine-4-carboxamide

To a stirred solution of N 1-cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (500 mg, 3.01 mmol) in DMF (3 mL) at room temperature under an inert atmosphere was added 6-chloro Pyrazine-4-carboxylic acid (475 mg, 3.01 mmol), HATU (1.37 g, 3.61 mmol) and ethyldiisopropylamine (2.2 mL, 12.04 mmol). The reaction mixture was stirred at room temperature for 4 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 6-chloro- N- (2- (cyclopropylamino) -4-fluoro) as a brown solid. Phenyl) pyrazine-4-carboxamide (550 mg, 1.79 mmol, 60%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.96 (s, 1H), 9.63 (d, J = 1.4Hz, 1H), 8.36 (d, J = 1.2Hz, 1H), 7.13 (dd, J = 8.4, 6.7 Hz, 1H), 6.75 (dd, J = 11.7, 2.7 Hz, 1H), 6.43 (td, J = 8.5, 2.7 Hz, 1H), 6.14 (s, 1H), 2.37-2.33 (m, 1H ), 0.77-0.73 (m, 2H), 0.46-0.42 (m, 2H).

LC-MS: m / z 305.0 [MH] ⁺ at 3.00 RT (83.53% purity).

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole (Ex.3)

Under an inert atmosphere, 6-chloro- N- (2- (cyclopropylamino) -4-fluorophenyl) pyrazine-4-carboxamide (550 mg, 1.79 mmol) in CH _{2 was added} at room temperature. A stirred solution in Cl ₂ (10 mL) was added dropwise trifluoroacetic acid (0.6 mL). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with a saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 2- (6-chloropyrazin-4-yl) -1-cyclopropyl- as an off-white solid. 6-Fluoro-1 H -benzo [d] imidazole Ex. 3 (200 mg, 0.69 mmol, 38%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.81 (dd, J = 9.0, 4.9Hz, 1H), 7.58 (dd, J = 9.0, 2.0 Hz, 1H), 7.21 (td, J = 9.3, 2.2 Hz, 1H), 3.97-3.93 (m, 1H), 1.22-1.17 (m, 2H), 0.83-0.79 (m, 2H).

LC-MS: m / z 288.9 [M + H] ⁺ at 2.59 RT (98.16% purity).

HPLC: 98.76%.

5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carbonitrile (Ex.2)

Under an inert atmosphere, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex.2 (100 mg, 0.35 mmol) in a stirred solution of DMF (1 mL) was added Zn (CN) ₂ (24 mg, 0.21 mmol). The reaction mixture was degassed under argon for 10 min. Pd ₂ (dba) ₃ (16 mg, 0.02 mmol) and Pd (dppf) Cl ₂ (13 mg, 0.02 mmol) were added at room temperature and the reaction mixture was degassed under argon for 5 min. The reaction mixture was heated to 100 ° C and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with EtOAc (40 mL), filtered through a celite pad and the celite bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d] as an off-white solid. [ D ] Imidazol-2-yl) pyridazin-3-carbonitrile Ex. 2 (30 mg, 0.11 mmol, 31%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.06 (d, J = 1.7Hz, 1H), 8.92 (d, J = 1.7Hz, 1H), 7.83 (dd, J = 8.7,4.9Hz, 1H) , 7.59 (dd, J = 9.0, 2.0 Hz, 1H), 7.25-7.20 (m, 1H), 3.98-3.93 (m, 1H), 1.24-1.19 (m, 2H), 0.82-0.78 (m, 2H) .

LC-MS: m / z 279.8 [M + H] ⁺ at 2.92 RT (99.44% purity).

HPLC: 99.21%.

[Example 4]

1-cyclopropyl-6-fluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 4)

Under an inert atmosphere, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazole Ex.3 (300mg, 1.04 mmol) A stirred solution of a mixture of 1,4-dioxane (15 mL) and water (2 mL) was added potassium carbonate (431 mg, 3.12 mmol) and 4,4,5,5-tetramethyl-2-vinyl -1,3,2-dioxaborolane (160 mg, 1.04 mmol). The reaction mixture was degassed under argon for 15 min. To this was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (8.5 mg, 0.01 mmol) at room temperature. The reaction mixture was heated to 80 ° C and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was diluted with EtOAc (60 mL), filtered through a pad of celite and the celite bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1-cyclopropyl-6-fluoro-2- (6-vinylpyridazine- 4-yl) -1H-benzo [ d ] imidazole Ex. 4 (150 mg, 0.53 mmol, 51%).

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 9.68 (d, J = 1.7 Hz, 1H), 8.44 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 9.0, 4.9 Hz, 1H) , 7.55 (dd, J = 9.0, 2.3Hz, 1H), 7.21-7.09 (m, 2H), 6.52 (d, J = 17.6Hz, 1H), 5.80 (d, J = 11.0Hz, 1H), 3.97- 3.93 (m, 1H), 1.20-1.14 (m, 2H), 0.77-0.72 (m, 2H).

LC-MS: m / z 280.9 [M + H] ⁺ at 2.43 RT (93.90% purity).

HPLC: 95.00%.

[Example 5]

5- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (Ex.5)

At room temperature, in a steel high-pressure tank to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex.3 (200mg , 0.69mmol) was stirred in MeOH (3mL) was added in the sodium acetate (171mg, 2.08mmol), 1,1 ' - ferrocene group - bis (diphenylphosphine) (19mg, 0.03mmol) and palladium acetate ( II) (7.8 mg, 0.03 mmol). The steel high-pressure tank was filled with CO gas (15 bar pressure). The resulting reaction mixture was stirred at 50 ° C. for 2 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d] as an off-white solid. [ D ] Midazol-2-yl) pyridazin-3-carboxylic acid methyl ester Ex. 5 (70 mg, 0.22 mmol, 32%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.04 (d, J = 2.0Hz, 1H), 8.74 (d, J = 2.0Hz, 1H), 7.82 (dd, J = 9.0,4.9Hz, 1H) , 7.57 (dd, J = 9.1, 2.5 Hz, 1H), 7.21 (td, J = 9.3, 2.3 Hz, 1H), 4.03 (s, 3H), 3.99-3.95 (m, 1H), 1.23-1.18 (m , 2H), 0.82-0.78 (m, 2H).

LC-MS: m / z 312.9 [M + H] ⁺ at 2.36 RT (95.19% purity).

HPLC: 99.01%.

[Example 6]

1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole (Ex. 6)

Under an inert atmosphere, 1-cyclopropyl-6-fluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex.4 (70mg, A stirred solution of 0.25 mmol) in ethyl acetate (8 mL) was added triethylamine (cat.) And 10% Pd / C (50% wet, 20 mg). The reaction mixture was vented and stirred at room temperature under a hydrogen atmosphere (ball pressure) for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6-ethylpyrazine-4- as an off-white solid. ) -6-fluoro-1 H -benzo [ d ] imidazole Ex. 6 (50 mg, 0.18 mmol, 67%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.66 (d, J = 2.1Hz, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.78 (dd, J = 8.8, 4.9Hz, 1H) , 7.55 (dd, J = 9.0, 2.4Hz, 1H), 7.22-7.14 (m, 1H), 3.95-3.90 (m, 1H), 3.07 (q, J = 7.6Hz, 2H), 1.37 (t, J = 7.7Hz, 3H), 1.21-1.15 (m, 2H), 0.77-0.71 (m, 2H).

LC-MS: m / z 282.9 [M + H] ⁺ at 2.37 RT (98.84% purity).

HPLC: 98.29%.

[Example 7]

1- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl-1- Alcohol (Ex.7)

5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-2 (50mg, 0.18 To a stirred solution of THF (3 mL) was added trimethyl (trifluoromethyl) silane (0.05 mL, 0.35 mmol). Cesium fluoride (81 mg, 0.53 mmol) was added and the reaction was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1- (5- (1-cyclopropyl-6-fluoro-1 H ) as an off-white solid. -Benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2,2-trifluoroethyl-1-ol Ex. 7 (15 mg, 0.04 mmol, 24%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.83 (d, J = 2.1Hz, 1H), 8.57 (d, J = 2.1Hz, 1H), 7.76 (dd, J = 8.9,4.8Hz, 1H), 7.52 (dd, J = 8.8, 2.3Hz, 1H), 7.20-7.13 (m, 1H), 5.54 (q, J = 6.9Hz, 1H), 3.90-3.85 (m, 1H), 1.33-1.20 (m, 2H), 0.87-0.79 (m, 2H).

LC-MS: m / z 352.9 [M + H] ⁺ at 2.59 RT (96.11% purity).

HPLC: 93.29%.

N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propanamide (Ex. 8)

To (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methylamine Int-3 at 0 ° C under an inert atmosphere. (140 mg, 0.49 mmol) in a stirred solution of CH ₂ Cl ₂ (5 mL) was added propanyl chloride (0.05 mL, 0.59 mmol) and triethylamine (0.14 mL, 0.1 mmol). The reaction mixture was stirred at 0 ° C for 3 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative high performance liquid chromatography (HPLC) to obtain N -((5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] Imidazol-2-yl) pyridazin-3-yl) methyl) propanamide Ex. 8 (40 mg, 0.12 mmol, 24%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.72 (d, J = 1.4Hz, 1H), 8.60 (br t, J = 5.1Hz, 1H), 8.13 (d, J = 1.4Hz, 1H), 7.79 (dd, J = 8.7,4.9Hz, 1H), 7.54 (dd, J = 9.0,2.0Hz, 1H), 7.18 (td, J = 9.8,2.3Hz, 1H), 4.67 (d, J = 6.1Hz , 2H), 3.89-3.84 (m, 1H), 2.22 (q, J = 7.5Hz, 2H), 1.25-1.16 (m, 2H), 1.04 (t, J = 7.7Hz, 3H), 0.77-0.71 ( m, 2H).

LC-MS: m / z 340.1 [M + H] ⁺ at 2.07 RT (99.22% purity).

HPLC: 99.08%.

[Example 9]

((5- (1-Cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) urethane (Ex.9)

To (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methylamine Int-3 at 0 ° C under an inert atmosphere. (125 mg, 0.44 mmol) in THF (6 mL) was added as a stirred solution of ethyl chloroformate (0.05 mL, 0.53 mmol) and triethylamine (0.12 mL, 0.88 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give ((5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) as an off-white solid. Methyl) urethane Ex. 9 (40 mg, 0.11 mmol, 26%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.75 (d, J = 2.1Hz, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.93 (br t, J = 6.0Hz, 1H), 7.79 (dd, J = 8.9,4.9Hz, 1H), 7.55 (dd, J = 9.1,2.4Hz, 1H), 7.22-7.15 (m, 1H), 4.60 (d, J = 6.1Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.91-3.84 (m, 1H), 1.22-1.16 (m, 5H), 0.78-0.73 (m, 2H).

LC-MS: m / z 356.1 [M + H] ⁺ at 2.33 RT (98.62% purity).

HPLC: 99.15%.

[Example 10]

4- (5- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) morpholine (Ex.10)

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex. 3 (150 mg, 0.52 mmol) in a stirred solution of ethanol (0.9 mL) was added triethylamine (0.11 mL, 0.78 mmol) and morpholine (0.07 mL, 0.78 mmol). The reaction mixture was heated to 90 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 100% EtOAc) to give 4- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d] as an off-white solid. [ D ] Imidazol-2-yl) pyridazin-3-yl) morpholine Ex. 10 (40 mg, 0.12 mmol, 23%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.14 (s, 1H), 7.81-7.71 (m, 2H), 7.53 (br d, J = 7.8Hz, 1H), 7.16 (br t, J = 7.1 Hz, 1H), 3.93-3.91 (m, 1H), 3.83-3.61 (m, 8H), 1.18-1.16 (m, 2H), 0.75-0.73 (m, 2H).

LC-MS: m / z 340.0 [M + H] ⁺ at 2.33 RT (97.11% purity).

HPLC: 97.09%.

[Example 11]

1-cyclopropyl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin-1-yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole ( Ex.11)

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex.3 (50mg, 0.17 mmol) in a stirred solution of EtOH (0.3 mL) was added triethylamine (0.036 mL, 0.26 mmol) and 1- (4-fluorophenyl) piperazine (47 mg, 0.26 mmol). The reaction mixture was stirred at 90 ° C for 7 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to give 1-cyclopropyl-6-fluoro-2- (6- (4- (4) as an off-white solid. - fluorophenyl) piperazin-1-yl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.11 (40mg, 0.09mmol, 53% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.13 (d, J = 1.6Hz, 1H), 7.80 (d, J = 1.5Hz, 1H), 7.77 (dd, J = 8.9, 4.9Hz, 1H) , 7.54 (dd, J = 9.1, 2.4Hz, 1H), 7.20-7.14 (m, 1H), 7.12-7.02 (m, 4H), 3.96-3.92 (m, 1H), 3.89-3.83 (m, 4H) , 3.28-3.24 (m, 4H), 1.21-1.15 (m, 2H), 0.78-0.72 (m, 2H)

LC-MS: m / z 433.1 [M + H] ⁺ at 2.38 RT (99.63% purity).

HPLC: 96.82%.

[Example 12]

5- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxaldehyde (Int-2)

To 1-cyclopropyl-6-fluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex.4 (600mg, 2.14 mmol) in a stirred solution of acetone: third butanol (tBuOH): water (1: 1: 1, 30 mL) was added sodium periodate (912 mg, 4.28 mmol) and osmium tetraoxide (2.5 wt% in toluene , 3mL). The reaction mixture was stirred at 0 ° C for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered and the filter was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to give 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d] as a brown solid. [ D ] Imidazol-2-yl) pyridazin-3-carboxaldehyde Int-2 (400 mg, 1.41 mmol, 66%).

¹ H NMR (500MHz, CDCl ₃ ): δ 10.52 (s, 1H), 10.08 (s, 1H), 8.65 (s, 1H), 7.81 (dd, J = 9.0, 4.9Hz, 1H), 7.35 (dd, J = 8.4, 2.3 Hz, 1H), 7.17-7.12 (m, 1H), 3.78-3.67 (m, 1H), 1.39-1.30 (m, 2H), 0.94-0.82 (m, 2H)

1- [5- (1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl) pyrazin-3-yl] ethan-1-ol

Under an inert atmosphere, at the temperature of -78 ° C, 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-2 (200mg, A stirred solution of 0.70 mmol) in THF (6 mL) was added dropwise with methyl magnesium bromide (2M in diethyl ether, 0.35 mL, 0.70 mmol). The reaction mixture was stirred at -78 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH ₂ Cl ₂ ) to obtain 1- [5- (1-cyclopropyl-6-fluoro- 1H-1,3-benzodiazol-2-yl) pyrazin-3-yl] ethan-1-ol (150 mg, 0.50 mmol, 71%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.72 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 9.0, 4.9Hz, 1H), 7.55 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.14 (m, 1H), 5.78 (d, J = 4.6 Hz, 1H), 5.16-5.05 (m, 1H), 3.95-3.90 (m, 1H), 1.52 (d, J = 6.7Hz, 3H), 1.25-1.15 (m, 2H), 0.77-0.75 (m, 2H)

1- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one

Under an inert atmosphere, 1- [5- (1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl) pyridazin-3-yl] ethyl- A stirred solution of 1-alcohol (100 mg, 0.33 mmol) in CH ₂ Cl ₂ (10 mL) was added Dess-Martin periodinane (213 mg, 0.51 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 50 mL). The organic layer was washed with a saturated sodium bicarbonate solution (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH ₂ Cl ₂ ) to obtain 1- (5- (1-cyclopropyl-6-fluoro-) as an off-white solid. 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one (80 mg, 0.27 mmol, 81%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.04 (s, 1H), 8.64 (s, 1H), 7.82 (dd, J = 9.0, 4.9Hz, 1H), 7.57 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.11 (m, 1H), 4.02-3.91 (m, 1H), 2.87 (s, 3H), 1.20-1.15 (m, 2H), 0.79-0.76 (m, 2H)

2- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) propan-2-ol (Ex. 12)

Under an inert atmosphere, at 1- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl- To a stirred solution of 1-ketone (60 mg, 0.20 mmol) in THF (2 mL) was added methyl magnesium bromide (2M in diethyl ether, 0.1 mL, 0.20 mmol) dropwise. The reaction mixture was stirred at -78 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give 2- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl as an off-white solid. ) Prop -2-ol Ex. 12 (15 mg, 0.05 mmol, 24%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.65 (s, 1H), 8.57 (s, 1H), 7.73 (dd, J = 8.9, 4.8Hz, 1H), 7.50 (dd, J = 8.8, 2.4Hz , 1H), 7.21-7.08 (m, 1H), 3.91-3.76 (m, 1H), 1.71 (s, 6H), 1.30-1.18 (m, 2H), 0.83-0.76 (m, 2H)

LC-MS: m / z 313 [M + H] ⁺ at 2.19 RT (95.83% purity).

HPLC: 95.47%.

[Example 13]

5- (1-cyclopropyl-6-fluoro -1 H - benzo [d] imidazol-2-yl) - N - (tetrahydro -2 H - pyran-4-yl) pyridazin-3-amine (Ex.13)

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex. 3 (150 mg, 0.52 mmol) in a stirred solution of EtOH (1.5 mL) was added triethylamine (0.2 mL, 1.56 mmol) and tetrahydro- 2H -piperan-4-amine (105 mg, 1.04 mmol). The reaction mixture was stirred at reflux for 16 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: EtOAc) to give 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole-2- as an off-white solid. yl) - N - (tetrahydro -2 H - pyran-4-yl) pyridazin-3-amine Ex.13 (40mg, 0.11mmol, 22% ).

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 9.01 (s, 1H), 7.74 (dd, J = 8.7, 4.9 Hz, 1H), 7.51 (dd, J = 9.1, 2.5 Hz, 1H), 7.41 ( s, 1H), 7.18-7.11 (m, 1H), 7.07 (d, J = 7.2Hz, 1H), 4.17-4.07 (m, 1H), 3.93-3.86 (m, 2H), 3.80-3.75 (m, 1H), 3.49-3.44 (m, 2H), 2.05-1.95 (m, 2H), 1.59-1.42 (m, 2H), 1.30-1.02 (m, 2H), 0.87-0.74 (m, 2H)

LC-MS: m / z 354 [M + H] ⁺ at 1.74 RT (97.97% purity).

HPLC: 97.95%.

[Example 14]

[Program]

N- (2- (cyclopropylamino) -4-fluorophenyl) pyridin-4-carboxamide

To a stirred solution of N 1-cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (500 mg, 3.01 mmol) in DMF (5 mL) at 0 ° C under an inert atmosphere was added oxoline- 4-Formic acid (524 mg, 3.01 mmol), HATU (1.71 g, 4.51 mmol) and diisopropylethylamine (1 mL, 6.02 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (2- (cyclopropylamino) -4-fluorophenyl) fluorene as a brown solid. Porphyrin-4-methylamidine (500 mg, crude), which was used in the next step without further purification.

LC-MS: m / z 322.9 [M + H] ⁺ at 2.71 RT (38.30% purity).

4- (1-Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) phosphonium (Ex.14)

Under an inert atmosphere, N- (2- (cyclopropylamino) -4-fluorophenyl) pyridin-4-formamidine (400 mg, 1.24 mmol) in EtOH (5 mL) was added at room temperature. The solution was stirred and 6N HCl (4 mL) was added. The reaction mixture was stirred at 80 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give 4- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridoline Ex.14 (160mg, 0.52 mmol, 43%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.69 (s, 1H), 8.65 (d, J = 8.2Hz, 1H), 8.23 (d, J = 8.5Hz, 1H), 8.12-8.07 (m, 1H ), 8.01-7.97 (m, 1H), 7.82-7.79 (m, 1H), 7.58 (dd, J = 8.8, 2.3Hz, 1H), 7.25-7.18 (m, 1H), 3.76-3.71 (m, 1H) ), 0.98-0.93 (m, 2H), 0.65-0.54 (m, 2H)

LC-MS: m / z 304.9 [M + H] ⁺ at 2.59 RT (99.51% purity).

HPLC: 99.30%.

[Example 15]

N- (2- (cyclopropylamino) -4-fluorophenyl) -6-methylpyrazine-4-carboxamide

To a stirred solution of 6-methylpyrazine-4-carboxylic acid (174 mg, 1.0 mmol) in DMF (3 mL) at 0 ° C. under an inert atmosphere was added N 1-cyclopropyl-5-fluorobenzene-1, 2-diamine Int-1 (166 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol), and diisopropylethylamine (1.38 mL, 4 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (2- (cyclopropylamino) -4-fluorophenyl)-as a brown solid. 6-methylpyrazine-4-carboxamide (250 mg, crude material).

LC-MS: m / z 287.2 [M + H] ⁺ at 3.53 RT (54.60% purity).

1-cyclopropyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.15)

Under an inert atmosphere, N- (2- (cyclopropylamino) -4-fluorophenyl) -6-methylpyrazine-4-carboxamide (250 g, 0.87 mmol) in EtOH (1.5 mL) of the stirred solution was added 6N HCl (3.5 mL). The reaction mixture was stirred at 80 ° C for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 4-5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-6-fluoro-2- (6-formaldehyde) as an off-white solid. pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.15 (80mg, 0.29mmol, 34% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.64 (s, 1H), 8.21 (s, 1H), 7.74 (dd, J = 9.0, 4.6Hz, 1H), 7.51 (dd, J = 8.8, 2.1Hz , 1H), 7.19-7.13 (m, 1H), 3.89-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.23 (m, 2H), 0.86-0.79 (m, 2H)

LC-MS: m / z 268.9 [M + H] ⁺ at 2.19 RT (95.85% purity).

HPLC: 97.59%.

[Example 16]

N- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethanesulfonamide (Ex. 16)

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex. 3 (100 mg, 0.34 mmol) in 1,4-dioxane A stirred solution in alkane (4 mL) was added ethanesulfonamide (57 mg, 0.52 mmol) and cesium carbonate (283 mg, 0.86 mmol) and the mixture was rinsed under argon for 5 min. Pd (OAc) ₂ (7.8 mg, 0.004 mmol) and Xanthphos (30 mg, 0.05 mmol) were then added to the reaction mixture. The reaction mixture was heated to 120 ° C and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (50mL) and diluted with 10% MeOH: extracted with _{CH 2 Cl 2 (2 x 50mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH ₂ Cl ₂ ) to obtain N- (5- (1-cyclopropyl-6-fluoro-) as a colorless slurry. 1H -Benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethanesulfonamide Ex. 16 (30 mg, 0.08 mmol, 24%).

¹ H NMR (400MHz, CD ₃ OD): δ 8.96 (brs, 1H), 8.45 (brs, 1H), 7.76-7.73 (m, 1H), 7.50 (dd, J = 8.8, 2.3 Hz, 1H), 7.25 -7.12 (m, 1H), 3.79-3.73 (m, 1H), 3.30-3.21 (m, 2H), 1.46-1.37 (m, 5H), 1.03-0.82 (m, 2H)

LC-MS: m / z 362 [M + H] ⁺ at 2.04 RT (95.41% purity).

HPLC: 94.11%.

[Example 17]

6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyrazine-4-carboxamide

To a stirred solution of 4-amino-3- (ethylamino) benzonitrile Int-4 (322 mg, 2 mmol) in DMF (6 mL) at room temperature under an inert atmosphere was added 6-chloropyridazine- 4-Formic acid (316 mg, 2 mmol), HATU (1.14 g, 3 mmol) and ethyl diisopropylamine (1.38 mL, 8 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 6-chloro-N- (4-cyano-2- (ethylamino) phenyl) pyridazine as an off-white solid- 4-formamidine (350 mg, crude material).

LC-MS: m / z 300.1 [MH] - in 2.07 RT (18.03% purity).

2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.17)

Under an inert atmosphere, 6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyridazine-4-carboxamide (350 mg, 1.16 mmol) in CH _{2 was added} at room temperature. Trifluoroacetic acid (TFA) (1 mL) was added dropwise to the stirred solution in Cl ₂ (3 mL). The reaction mixture was stirred at room temperature for 6 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 2- (6-chloropyrazin-4-yl) -1-ethyl- 1H -benzo [ d ] imidazole-6-carbonitrile as an off-white solid. Ex. 17 (25 mg, 0.08 mmol, 7.5%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.63 (d, J = 1.9Hz, 1H), 8.27 (d, J = 1.8Hz, 2H), 7.93 (dd, J = 8.4, 0.6Hz, 1H), 7.69 (dd, J = 8.5,1.4Hz, 1H), 4.56-4.51 (m, 2H), 1.51 (t, J = 7.3Hz, 3H)

LC-MS: m / z 284.2 [M + H] ⁺ at 3.50 RT (99.67% purity).

HPLC: 99.48%.

[Example 18]

2- (4- (5- (1-cyclopropyl-6-fluoro -1 H - benzo [d] imidazol-2-yl) pyridazin-3-yl) piperazin-1-yl) - N - Isopropylacetamide (Ex.18)

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex. 3 (56 mg, 0.19 mmol) in a stirred solution of EtOH (2 mL) was added triethylamine (0.04 mL, 0.28 mmol) and N -isopropyl-2- (4- (2,2,2-trifluoroethylfluorenyl) -415- Piperazin-1-yl) acetamide (60 mg, 0.27 mmol). The reaction mixture was stirred at reflux for 16 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by preparative HPLC to give 2- (4- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazine- 3-yl) piperazin-1-yl) -N -isopropylacetamidamine Ex. 18 (12 mg, 0.02 mmol, 14%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.08 (s, 1H), 7.76 (s, 1H), 7.72 (dd, J = 8.9,4.8Hz, 1H), 7.50 (dd, J = 8.8, 2.5Hz , 1H), 7.15 (dt, J = 9.3, 2.4Hz, 1H), 4.13-4.02 (m, 1H), 3.87-3.81 (m, 4H), 3.34-3.31 (m, 1H), 3.10 (s, 2H ), 2.73-2.69 (m, 4H), 1.28-1.23 (m, 2H), 1.20 (d, J = 6.7Hz, 6H), 0.86-0.80 (m, 2H)

LC-MS: m / z 438.4 [M + H] ⁺ at 3.76 RT (94.38% purity).

HPLC: 94.23%.

[Example 19]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6-methylpyrazine-4-carboxamide

To a stirred solution of N 1-cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (184 mg, 1.0 mmol) in DMF (3 mL) at 0 ° C under an inert atmosphere. 6-methylpyrazine-4-carboxylic acid (174 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol) and diisopropylethylamine (1.38 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (2- (cyclopropylamino) -4,5-difluorobenzene as a brown slurry. ) -6-methylpyrazine-4-carboxamide (220 mg, crude material).

LC-MS: m / z 305.2 [M + H] ⁺ at 3.78 RT (44.76% purity).

1-cyclopropyl-5,6-difluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.19)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6-methylpyrazine-4-carboxamide (220 mg, 0.72 mmol) at room temperature under an inert atmosphere ) To a stirred solution in EtOH (1.5 mL) was added 6N HCl (3.5 mL). The reaction mixture was stirred at 80 ° C for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3-5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (off-white solid) 6-methyl-pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.19 (60mg, 0.20mmol, 29% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.63 (d, J = 1.9Hz, 1H), 8.20 (d, J = 2.1Hz, 1H), 7.72 (dd, J = 10.1,7.1Hz, 1H), 7.62 (dd, J = 10.4,7.3Hz, 1H), 3.90-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.24 (m, 2H), 0.85-0.80 (m, 2H)

LC-MS: m / z 286.9 [M + H] ⁺ at 2.32 RT (99.57% purity).

HPLC: 99.70%.

[Example 20]

4- (2-ethoxy-2- pendantoxyethyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of piperazine-1-carboxylic acid third butyl ester (2 g, 10.7 mmol) in DMF (14 mL) at room temperature under inert atmosphere was added potassium carbonate (3.71 g, 26.8 mmol) and ethyl bromoacetate (1.2 mL, 10.8 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 4- (2-ethoxy-2- pendoxyethyl) piperazine-1-carboxylic acid tert-butyl as a yellow oil. Esters (2.8 g, 10.29 mmol, 95%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 4.12-4.00 (m, 2H), 3.30 (s, 4H), 3.23 (s, 2H), 2.45 (t, J = 4.6Hz, 4H), 1.39 ( s, 9H), 1.18 (t, J = 7.1Hz, 3H)

2- (4-third butoxycarbonyl) piperazin-1-yl) acetic acid

At 0 ° C, tert-butyl 4- (2-ethoxy-2- pendoxyethyl) piperazine-1-carboxylic acid (2.8 g, 10.29 mmol) in THF: MeOH: water (3: 1 : 1,30 mL) of the stirred solution was added lithium hydroxide (1.29 g, 30.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified with 5% citric acid solution to pH 4-5 and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 2- (4- (third butoxycarbonyl) piperazin-1-yl) acetic acid (200 mg, crude material as a yellow oil). ), Which was used in the next step without further purification.

LC-MS: m / z 245.1 [MH] ⁺ at 1.06 RT (71.81% purity).

4- (2-Pendoxy-2- (pyrrolidin-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 2- (4- (third butoxycarbonyl) piperazin-1-yl) acetic acid (500 mg, 2.04 mmol) in CH ₂ Cl ₂ (15 mL) at room temperature under an inert atmosphere. Pyrrolidine (0.2 mL, 2.45 mmol), HATU (1.1 g, 3.07 mmol), and ethyldiisopropylamine (1.5 mL, 8.19 mmol). The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (30mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 30mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to give 4- (2- pendantoxy-2- (pyrrolidin-1-yl) as a brown solid. ) Ethyl) piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol, 16%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 3.43 (t, J = 6.7Hz, 2H), 3.31 (s, 2H), 3.29-3.25 (m, 4H), 2.43 (brs, 4H), 1.87- 1.82 (m, 2H), 1.78-1.71 (m, 2H), 1.39 (s, 9H), 1.29-1.23 (m, 2H)

4- (2-Pendoxy-2- (pyrrolidin-1-yl) ethyl) piperazin-1-yl 2,2,2-trifluoroacetate

To a tert-butyl 4- (2-oxo-2- (pyrrolidin-1-yl) ethyl) piperazine-1-carboxylic acid (100 mg, 0.33 mmol) in CH at room temperature under an inert atmosphere. in the ₂ Cl ₂ (1mL) was added dropwise with stirring trifluoroacetic acid (0.5mL). The reaction mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The crude material was washed with diethyl ether (2 x 5 mL) to give 4- (2- pendantoxy-2- (pyrrolidin-1-yl) ethyl) piperazin-1-yl 2,2,2 as a white solid -Trifluoroacetate (120 mg as TFA salt).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 3.72 (brs, 1H), 3.40-3.37 (m, 4H), 3.33-3.30 (m, 4H), 3.24 (s, 2H), 3.08 (brs, 4H ), 1.92-1.85 (m, 2H), 1.81-1.76 (m, 2H)

2- (4- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazin-1-yl) -1- (Pyrrolidin-1-yl) ethan-1-one (Ex. 20)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole Ex.3 (100mg, 0.34 mmol) in a stirred solution in EtOH (2 mL) was added triethylamine (0.14 mL, 1.04 mmol) and 4- (2-sideoxy-2- (pyrrolidin-1-yl) ethyl) piperazine-1- 2,2,2-trifluoroacetate (34 mg, 0.17 mmol). The reaction mixture was stirred at 80 ° C for 32 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by preparative HPLC to give 2- (4- (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazine- 3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan- 1-one Ex . 20 (20 mg, 0.041 mmol, 13%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.16 (s, 1H), 7.75-7.71 (m, 1H), 7.47 (s, 1H), 7.30 (dd, J = 8.6, 2.4Hz, 1H), 7.11- 7.06 (m, 1H), 3.87-3.85 (m, 4H), 3.63-3.57 (m, 1H), 3.53-3.43 (m, 4H), 3.28 (s, 2H), 2.83 (brs, 4H), 2.03- 1.93 (m, 2H), 1.89-1.84 (m, 2H), 1.30-1.22 (m, 2H), 0.88-0.80 (m, 2H)

LC-MS: m / z 450.2 [M + H] ⁺ at 1.74 RT (97.66% purity).

HPLC: 97.81%.

[Examples 21 & 22]

6-Chloro- N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide

To a stirred solution of N 1-cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (1 g, 5.43 mmol) in DMF (10 mL) at room temperature under an inert atmosphere. 6-chloropyrazine-4-carboxylic acid (1.03 g, 6.52 mmol), HATU (2.48 g, 6.52 mmol), and diisopropylethylamine (3.9 mL, 21.72 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 0-2% MeOH / CH ₂ Cl ₂ ) to obtain 6-chloro-N- (2- (cyclopropylamino)) as a brown solid. -4,5-difluorophenyl) pyridazin-4-methylamidine (800 mg, 2.46 mmol, 45%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.50 (s, 1H), 7.95 (d, J = 1.6Hz, 1H), 7.74 (brs, 1H), 7.37 (dd, J = 10.5, 8.5Hz, 1H) , 7.06 (dd, J = 12.4, 7.7Hz, 1H), 4.16-4.03 (m, 1H), 2.51-2.40 (m, 1H), 0.83-0.75 (m, 2H), 0.56-0.47 (m, 2H)

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 22)

Under an inert atmosphere, 6-chloro- N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide (700 mg, 2.16 mmol) was added at room temperature. To the stirred solution in EtOH (7 mL) was added 6N HCl (10.5 mL). The reaction mixture was stirred at 70 ° C for 30 min. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to give 2- (6-chloropyridazin-4-yl) -1-cyclopropane as an off-white solid. -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 22 (280 mg, 0.91 mmol, 42%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.78 (d, J = 1.9Hz, 1H), 8.15 (d, J = 1.9Hz, 1H), 7.60 (dd, J = 10.0,7.2Hz, 1H), 7.44 (dd, J = 9.5, 6.9Hz, 1H), 3.70-3.62 (m, 1H), 1.41-1.33 (m, 2H), 0.93-0.84 (m, 2H)

LC-MS: m / z 306.9 [M + 1] ⁺ at 2.52 RT (99.86% purity).

HPLC: 99.51%.

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N -methylpyrazine-3-amine (Ex. 21)

Dissolve 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (600mg, 1.96mmol ) in 2M forma Amine solution (2M in diethyl ether, 3 mL) and the reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH ₂ Cl ₂ ) to obtain 5- (1-cyclopropyl-5,6-difluoro) as a pale green solid. -1 H - benzo [d] imidazol-2-yl) -N- methyl-pyridazin-3-amine Ex.21 (50mg, 0.16mmol, 8% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.13 (d, J = 1.8Hz, 1H), 7.57 (dd, J = 10.2,7.3Hz, 1H), 7.41 (dd, J = 9.7,7.0Hz, 1H) , 7.20 (d, J = 1.8Hz, 1H), 5.03 (d, J = 4.5Hz, 1H), 3.59 (tt, J = 7.0, 3.6Hz, 1H), 3.12 (d, J = 5.1Hz, 3H) , 1.32-1.24 (m, 2H), 0.87-0.80 (m, 2H)

LC-MS: m / z 301.9 [M + 1] ⁺ at 1.76 RT (98.78% purity).

HPLC: 99.48%.

[Example 23]

1-cyclopropyl-5,6-difluoro-2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.23)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100 mg, 0.32 mmol) in a stirred solution of MeOH (5 mL) was added sodium methoxide (53 mg, 0.98 mmol). The reaction mixture was stirred at 70 ° C for 2 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-methoxy) as an off-white solid. pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.23 (40mg, 0.13mmol, 41% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.45 (s, 1H), 7.89-7.80 (m, 2H), 7.77 (s, 1H), 4.13 (s, 3H), 3.93-3.89 (m, 1H ), 1.23-1.12 (m, 2H), 0.82-0.70 (m, 2H)

LC-MS: m / z 302.9 [M + H] ⁺ at 2.30 RT (99.80% purity).

HPLC: 99.68%.

[Example 24]

1-cyclopropyl-5,6-difluoro-2- (6-isopropoxypyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 24)

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( A stirred solution of 70 mg, 0.23 mmol) in DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) in portions. The reaction mixture was stirred at 0 ° C for 30 min. To this reaction mixture was added propan-2-ol (27.5 mg, 0.46 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-isopropyl) as an off-white solid. pyridazin-4-yloxy) -1 H - benzo [d] imidazole Ex.24 (30mg, 0.09mmol, 40% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.39 (s, 1H), 7.89-7.80 (m, 2H), 7.67 (s, 1H), 5.57-5.51 (m, 1H), 3.93-3.89 (m , 1H), 1.42 (d, J = 6.1Hz, 6H), 1.20-1.11 (m, 2H), 0.86-0.68 (m, 2H)

LC-MS: m / z 330.9 [M + H] ⁺ at 2.88 RT (93.72% purity).

HPLC: 95.25%.

[Example 25]

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N , N -dimethylpyrazine-3-amine (Ex.25)

Dissolve 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (60mg, 0.19mmol) in 2M Methylamine solution (2M in THF, 3 mL) and the reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH ₂ Cl ₂ ) to obtain 5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) -N, N-dimethylpyrazine-3-amine Ex. 25 (16 mg, 0.05 mmol, 26%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.08 (s, 1H), 7.58 (dd, J = 10.2, 7.3Hz, 1H), 7.41 (dd, J = 9.7, 7.0Hz, 1H), 7.32 (s, 1H), 3.62-3.57 (m, 1H), 3.28 (s, 6H), 1.29-1.23 (m, 2H), 0.87-0.77 (m, 2H)

LC-MS: m / z 316.1 [M + 1] ⁺ at 1.81 RT (98.32% purity).

HPLC: 95.98%.

[Example 26]

2-bromo-1-ethyl-6-fluoro-1 H -indole

To a stirred solution of 2-bromo-6-fluoro-1H-indole (250 mg, 1.16 mmol) in DMF (2 mL) at room temperature under an inert atmosphere was added potassium carbonate (476 mg, 3.50 mmol), followed by Iodoethane (364 mg, 2.33 mmol). The reaction mixture was stirred at room temperature for 4 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 2-bromo-1-ethyl-6-fluoro-1 H -indole (280 mg, crude material) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.43 (dd, J = 8.6, 5.3 Hz, 1H), 6.98 (dd, J = 9.7, 2.3 Hz, 1H), 6.86-6.84 (m, 1H), 6.54 ( d, J = 0.8Hz, 1H), 4.21-4.16 (m, 2H), 1.34 (t, J = 7.2Hz, 3H)

1-ethyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (Ex. 26)

To a stirred solution of 2-bromo-1-ethyl-6-fluoro-1H-indole (200 mg, 0.83 mmol) in 1,4-dioxane (2 mL) was added (6-methylpyrazine-4- ) Boronic acid (214 mg, 1.24 mmol), sodium carbonate solution (2M, 0.5 mL) and rinsed under argon for 10 min. Subsequently, Pd (dppf) Cl ₂ (60 mg, 0.08 mmol) was added to the reaction mixture and the reaction mixture was stirred in a sealed tube at 80 ° C. for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-ethyl-6-fluoro-2- (6-methylpyrazine as a yellow solid. -4-yl) -1H-indole Ex. 26 (50 mg, 0.19 mmol, 20%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.25 (d, J = 2.0Hz, 1H), 7.76 (d, J = 2.1Hz, 1H), 7.61 (dd, J = 8.7,5.3Hz, 1H), 7.28 (dd, J = 10.1, 2.2Hz, 1H), 6.96-6.90 (m, 2H), 4.35-4.30 (m, 2H), 2.77 (s, 3H), 1.29 (t, J = 7.2Hz, 3H)

LC-MS: m / z 256 [M + H] ⁺ at 2.73 RT (98.24% purity)

HPLC: 97.70%

[Example 27]

1-cyclopropyl-5,6-difluoro-2- (6- (2,2,2-trifluoroethoxy) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex .27)

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1H-benzo [d] imidazole Ex.22 (70mg , 0.23 mmol) in a stirred solution of DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) in portions. The reaction mixture was stirred at 0 ° C for 30 min. To this reaction mixture was added 2,2,2-trifluoroethan-1-ol (46 mg, 0.46 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6- (2 2,2,2-trifluoroethoxy) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.27 (50mg, 0.13mmol, 62% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.55 (s, 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 5.39-5.27 (m, 2H), 3.96-3.93 (m , 1H), 1.21-1.13 (m, 2H), 0.82-0.69 (m, 2H)

LC-MS: m / z 370.9 [M + 1] ⁺ at 3.18 RT (99.73% purity).

HPLC: 98.32%.

[Example 28]

5- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) - N - (2- methoxyethyl) pyridazin-3-amine (Ex .28)

Under an inert atmosphere at room temperature, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1H-benzo [ d ] imidazole Ex.22 (50mg , 0.16 mmol) in THF (0.5 mL) was added to a stirred solution of 2-methoxyethyl-1-amine (0.5 mL, 75.11 mmol) and ethyldiisopropylamine (0.5 mL). The reaction mixture was stirred at 110 ° C for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material with CH ₂ Cl _2: hexanes: washing (1 9,10mL) to afford a pale yellow solid of 5- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) - N - (2- methoxyethyl) pyridazin-3-amine Ex.28 (40mg, 0.13mmol, 92% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.12 (s, 1H), 7.56 (dd, J = 10.1, 7.2Hz, 1H), 7.41 (dd, J = 9.7, 6.9Hz, 1H), 7.22 (s, 1H), 5.21 (brs, 1H), 3.76-3.73 (m, 2H), 3.69-3.64 (m, 2H), 3.61-3.59 (m, 1H), 3.41 (s, 3H), 1.31-1.25 (m, 2H), 0.87-0.81 (m, 2H)

LC-MS: m / z 346 [M + H] ⁺ at 1.80 RT (97.27% purity).

HPLC: 97.05%.

[Example 29]

N- (4-cyano-2- (cyclopropylamino) phenyl) -6-methoxypyrazine-4-carboxamide

To a stirred solution of 4-amino-3- (cyclopropylamino) benzonitrile Int-6 (300mg, 1.72mmol) in DMF (5mL) at room temperature under an inert atmosphere, add 6-methoxy Pyridazine-4-carboxylic acid (281 mg, 1.72 mmol), HATU (720 mg, 1.89 mmol), and ethyldiisopropylamine (0.8 mL, 5.17 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (4-cyano-2- (cyclopropylamino) phenyl) -6-methoxy as a yellow liquid. Dazin-4-methylamidine (300 mg, crude), which was used in the next step without further purification.

1-cyclopropyl-2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex. 29)

N- (4-cyano-2- (cyclopropylamino) phenyl) -6-methoxypyrazine-4-carboxamide (300 mg, crude material) at 0 ° C under an inert atmosphere. Trifluoroacetic acid (0.5 mL) was added dropwise to the stirred solution in CH ₂ Cl ₂ (10 mL). The reaction mixture was stirred at 0 ° C for 2 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The (5mL) residue diluted with water, (20mL) and basified with saturated sodium carbonate solution and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ C ₁₂ ) to obtain 1-cyclopropyl-2- (6-methoxypyridazine- 4- yl) -1 H - benzo [d] imidazole-6-carbonitrile Ex.29 (40mg, 0.13mmol, 14% ( two steps)).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.48 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.4Hz, 1H), 7.82 (s, 1H), 7.71 (dd, J = 8.4, 1.5Hz, 1H), 4.14 (s, 3H), 4.01-3.85 (m, 1H), 1.23-1.14 (m, 2H), 0.87-0.77 (m, 2H)

LC-MS: m / z 291.9 [M + H] ⁺ at 2.25 RT (95.84% purity).

HPLC: 97.16%.

[Example 30]

1- (2,2-dibromovinyl) -4-fluoro-2-nitrobenzene

At 0 ℃, under an inert atmosphere a solution of 4-fluoro-2-nitrobenzaldehyde (2g, 11.83mmol) in CH ₂ Cl ₂ (100mL) in the stirred solution was added carbon tetrabromide (5.8g, 17.75mmol) And triphenylphosphine (9.3 g, 35.50 mmol). The reaction mixture was stirred at 5 ° C for 2h. The progress of the reaction was monitored by TLC; the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1- (2,2-dibromovinyl) -4-fluoro-2-nitrobenzene (3.2 g, crude material), which was used in the next step without further purification.

2- (2,2-dibromovinyl) -5-fluoroaniline

To a stirred solution of 1- (2,2-dibromovinyl) -4-fluoro-2-nitrobenzene (3.2 g, 9.87 mmol) in EtOH (20 mL) was added SnCl ₂ under an inert atmosphere at RT. .H ₂ O (11.1 g, 46.29 mmol). The reaction mixture was stirred at reflux for 2 h. The progress of the reaction was monitored by TLC; the volatiles were concentrated under reduced pressure. The obtained residue was basified with potassium carbonate solution to a pH of about 10 and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2- (2,2-dibromovinyl) -5-fluoroaniline (2.1 g as a brown solid) , 7.14 mmol, 72%).

LC-MS: m / z 295.6 [M + 2H] ⁺ at 3.34 RT (96.98% purity)

N- (2- (2,2-dibromovinyl) -5-fluorophenyl) methanesulfonamide

To a stirred solution of 2- (2,2-dibromovinyl) -5-fluoroaniline (1 g, 3.40 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C, pyridine (0.54 mL) was added. , 6.80 mmol) and methanesulfonyl chloride (0.38 mL, 5.10 mmol). The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was quenched with NaHSO ₄ solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give N- (2- (2,2-dibromovinyl) -5-fluorobenzene as a brown solid. ) Methanesulfonamide (1.1 g, 2.94 mmol, 87%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.57 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.7,6.4Hz, 1H), 7.23 (dd, J = 10.4,2.3 Hz, 1H), 7.14 (dt, J = 8.4, 2.3 Hz, 1H), 3.06 (s, 3H)

2-bromo-6-fluoro-1 H -indole

To a stirred solution of N- (2- (2,2-dibromovinyl) -5-fluorophenyl) methanesulfonamide (200 mg, 0.53 mmol) in THF (2 mL) under an inert atmosphere at RT. 1M TBAF in THF (1 mL) was added. The reaction mixture was stirred in the microwave at 100 ° C for 5 min. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 2-bromo-6-fluoro-1H-indole 5 (100 mg, crude) as a brown solid , Which was used in the next step without further purification.

LC-MS: m / z 295.6 [M + 2H] ⁺ at 3.34 RT (96.98% purity)

2-bromo-1-cyclopropyl-6-fluoro-1 H -indole

To a stirred solution of 2-bromo-6-fluoro-1 H -indole 5 (400 mg, 1.86 mmol) in 1,2-dichloroethane (5 mL) at RT under inert atmosphere was added cyclopropylboronic acid. (321 mg, 3.73 mmol), sodium carbonate (571 mg, 5.60 mmol), copper acetate (371 mg, 1.86 mmol), and bipyridine (291 mg, 1.86 mmol). The reaction mixture was stirred in a sealed tube at 80 ° C for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2-bromo-1-cyclopropyl-6-fluoro- 1H -indole (brown solid) 300 mg, 1.19 mmol, 63%).

¹ H NMR (400MHz, CDCl ₃ ): δ 7.39 (dd, J = 8.6,5.4Hz, 1H), 7.23 (dd, J = 10.1,2.3Hz, 1H), 6.88-6.83 (m, 1H), 6.51 ( s, 1H), 3.14-3.09 (m, 1H), 1.27-1.19 (m, 2H), 1.13-1.08 (m, 2H)

1-cyclopropyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (Ex. 30)

To a stirred solution of 2-bromo-1-cyclopropyl-6-fluoro-1 H -indole (200 mg, 0.79 mmol) in 1,4-dioxane (5 mL) was added 3-methyl-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxopentyl-2-yl) pyrazine (261 mg, 1.19 mmol), sodium carbonate solution (2M, 0.5 mL) and under argon Rinse for 10 minutes. Pd (dppf) Cl ₂ (58 mg, 0.08 mmol) was then added to the reaction mixture and the reaction mixture was stirred in a sealed tube at 80 ° C. for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-6-fluoro-2- (6-methyl) as a pale yellow solid. pyridazin-4-yl) -1 H - indole Ex.30 (36mg, 0.13mmol, 17% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.42 (d, J = 2.1Hz, 1H), 7.97 (d, J = 2.1Hz, 1H), 7.60 (dd, J = 8.7,5.3Hz, 1H), 7.37 (dd, J = 10.0, 2.4Hz, 1H), 6.98 (s, 1H), 6.96-6.91 (m, 1H), 3.83-3.68 (m, 1H), 2.80-2.79 (m, 3H), 1.25- 1.09 (m, 2H), 0.78-0.63 (m, 2H)

LC-MS: m / z 267.9 [M + H] ⁺ at 2.78 RT (98.96% purity)

HPLC: 97.98%

[Example 31]

[Program]

N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) ethanesulfonamide (Ex. 31)

To (5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methylamine Int-3 at 0 ° C under an inert atmosphere. (30 mg, 0.10 mmol) in a stirred solution of THF (2 mL) was added ethanesulfonyl chloride (16 mg, 0.12 mmol) and triethylamine (0.03 mL, 0.21 mmol). The reaction mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give N -((5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3- as a white solid (Methyl) methyl) ethanesulfonamide Ex. 31 (15 mg, 0.04 mmol, 38%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.73 (s, 1H), 8.52 (s, 1H), 7.78-7.74 (m, 1H), 7.53 (dd, J = 8.9, 2.4Hz, 1H), 7.20 -7.14 (m, 1H), 4.71 (s, 2H), 3.87-3.82 (m, 1H), 3.24-3.19 (m, 2H), 1.47-1.31 (m, 5H), 0.89-0.80 (m, 2H)

LC-MS: m / z 376 [M + H] ⁺ at 2.21 RT (99.12% purity).

HPLC: 98.34%.

[Example 32]

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N- (2,2,2-trifluoroethyl) pyrazine-3- Amine (Ex. 32)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 80 mg, 0.26 mmol) in a stirred solution of NMP (1.2 mL) was added 2,2,2-trifluoroethyl-1-amine (1.2 mL). The reaction mixture was stirred in the microwave at 130 ° C for 6 minutes. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH ₂ Cl ₂ ) to obtain 5- (1-cyclopropyl-5,6-difluoro-1) as a pale yellow solid. H - benzo [d] imidazol-2-yl) - N - (2,2,2- trifluoroethyl) pyridazin-3-amine Ex.32 (15mg, 0.04mmol, 15% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.28 (s, 1H), 7.59 (dd, J = 10.1, 7.2Hz, 1H), 7.44 (dd, J = 9.6, 7.0Hz, 1H), 7.37 (s, 1H), 5.09 (t, J = 6.0Hz, 1H), 4.43-4.30 (m, 2H), 3.66-3.60 (m, 1H), 1.36-1.29 (m, 2H), 0.91-0.84 (m, 2H)

LC-MS: m / z 370 [M + H] ⁺ at 2.21 RT (97.23% purity).

HPLC: 97.15%.

[Example 33]

1-cyclopropyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole

Under an inert atmosphere at room temperature, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Example 22 (150 mg (0.50 mmol) in a stirred solution of 1,4-dioxane (3 mL) and water (0.5 mL) were added pinacol vinyl borate (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol). The reaction mixture was degassed with argon for 10 min, Pd (dppf) Cl ₂ (4 mg, 0.005 mmol) was added, and the reaction mixture was degassed with argon for another 10 min. The reaction mixture was heated to 80 ° C and stirred for 5 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-vinyl) as an off-white solid. pyridazin-4-yl) -1 H - benzo [d] imidazole (70mg, 0.23mmol, 48%) .

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7Hz, 1H), 5.82 (d, J = 11.4Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 33)

To 1-cyclopropyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (70 mg, A stirred solution of 0.23 mmol) in EtOAc (3 mL) was added 10% Pd / C (20 mg) and triethylamine (catalytic amount). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the pad was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6-ethylpyrazine-4- as an off-white solid. ) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 33 (35 mg, 0.11 mmol, 50%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.65 (s, 1H), 8.17 (s, 1H), 7.89-7.81 (m, 2H), 3.95-3.91 (m, 1H), 3.10-3.04 (m , 2H), 1.36 (t, J = 7.6Hz, 3H), 1.24-1.12 (m, 2H), 0.79-0.64 (m, 2H)

LC-MS: m / z 300.9 [M + H] ⁺ at 2.51 RT (98.98% purity).

HPLC: 97.01%.

[Example 34]

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.34)

1-Cyclopropyl-2- (6-methoxypyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 29 (60 mg, 0.20 mmol) in phosphorus chloride The stirred solution in osmium (POCl ₃ ) (0.38 mL, 4.13 mmol) was placed under an inert atmosphere at room temperature. The reaction mixture was heated to 100 ° C and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was basified with a saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 2- (6-chloropyrazin-4-yl) -1-cyclopropyl- as a white solid. 1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 34 (10 mg, 0.03 mmol, 16%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.82 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.68 (dd, J = 8.4, 1.5Hz, 1H), 3.95-3.90 (m, 1H), 1.36-1.29 (m, 2H), 0.94-0.84 (m, 2H)

LC-MS: m / z 296.2 [M + H] ⁺ at 3.28 RT (96.40% purity).

HPLC: 96.31%.

[Example 35]

3-cyclopropyl-2- pendantoxy-2,3-dihydro-1 H -benzo [ d ] imidazole-5-carbonitrile

To a stirred solution of 4-amino-3- (cyclopropylamino) benzonitrile Int-6 (500 mg, 2.89 mmol) in THF (10 mL) at room temperature under an inert atmosphere was added 1,1 ' -Carbonyldiimidazole (CDI) (702 mg, 4.33 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to obtain 3-cyclopropyl-2- pendantoxy-2,3-dihydro as an off-white solid. -1 H - benzo [d] imidazole-5-carbonitrile (200mg, 1.00mmol, 35%) .

¹ H NMR (500MHz, DMSO- d ₆ ): δ 11.29 (brs, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.0,1.3Hz, 1H), 7.09 (d, J = 8.1Hz, 1H), 2.91-2.85 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.83 (m, 2H)

2-bromo-1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile

Under an inert atmosphere, 2-bromo-3-cyclopropyl-2,3-dihydro-1 H -benzo [ d ] imidazole-5-carbonitrile (200 mg, 1.0 mmol) at 1, Phosphonium bromide (1.2 g, 4.02 mmol) was added to a stirred solution in 2-dichloroethane (DCE) (4 mL). The reaction mixture was heated to 80 ° C and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted, basified and extracted with _{CH 2 Cl 2 (2 x 30mL} ) with saturated sodium carbonate solution (30mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 2-bromo-3-cyclopropyl-2,3-dihydro-1 H -benzo [ d ] imidazole as a white solid. -5-carbonitrile (50 mg, 0.20 mmol, 19%), which was used in the next step without further purification.

LC-MS: m / z 261.8 [M +] ⁺ at 2.52 RT (96.21% purity).

1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.35)

Under an inert atmosphere, 2-bromo-3-cyclopropyl-2,3-dihydro-1 H -benzo [ d ] imidazole-5-carbonitrile (100 mg, 0.38 mmol) at 1, To a stirred solution in 4-dioxane (3 mL) was added 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl). Azine (126.9 mg, 0.57 mmol) and 2M aqueous sodium carbonate solution (0.3 mL, 0.64 mmol). The reaction mixture was degassed under argon for 10 min, Pd (dppf) Cl ₂ (23 mg, 0.03 mmol) was added, and the mixture was degassed under argon for another 10 min. The reaction mixture was heated to 90 ° C and stirred for 16 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-2- (6-methylpyrazin-4-yl) as an off-white solid. -1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 35 (20 mg, 0.07 mmol, 12%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.68 (d, J = 1.8Hz, 1H), 8.26 (s, 2H), 7.91 (d, J = 8.5Hz, 1H), 7.68 (dd, J = 8.4 , 1.4Hz, 1H), 3.94-3.90 (m, 1H), 2.86 (s, 3H), 1.36-1.25 (m, 2H), 0.90-0.81 (m, 2H)

LC-MS: m / z 275.9 [M + H] ⁺ at 2.02 RT (99.65% purity).

HPLC: 99.26%.

[Example 36]

1-cyclopropyl-5,6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 36)

Under an inert atmosphere, the 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 ( A solution of 50 mg, 0.16 mmol) in 1-methylpiperazine (0.5 mL) was stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (6 as a pale yellow solid. -(4-methylpiperazin-1-yl) pyrazin -4-yl) -1H-benzo [d] imidazole Ex. 36 (25 mg, 0.06 mmol, 41%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.13 (s, 1H), 7.57 (dd, J = 10.2, 7.3Hz, 1H), 7.46 (s, 1H), 7.41 (dd, J = 9.6, 7.0Hz, 1H), 3.86-3.74 (m, 4H), 3.63-3.57 (m, 1H), 2.64-2.52 (m, 4H), 2.37 (s, 3H), 1.30-1.25 (m, 2H), 0.85-0.81 ( m, 2H)

LC-MS: m / z 371 [M + H] ⁺ at 1.71 RT (98.46% purity).

HPLC: 97.35%.

[Example 37]

1-cyclopropyl-5,6-difluoro-2- (6- (piperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole

4- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 ° C under an inert atmosphere A stirred solution of piperazine-1-carboxylic acid third butyl ester Ex. 39 (200 mg, 0.43 mmol) in CH ₂ Cl ₂ (2 mL) was added trifluoroacetic acid (0.6 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was neutralized with a saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with diethyl ether: n-pentane (1: 1, 2 x 2 mL) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- (piperazin-1-yl) as a brown solid ) pyridazin-4-yl) -1 H - benzo [d] imidazole (90 mg of, crude), which was used without further purification in the next step.

LC-MS: m / z 357 [M + H] ⁺ at 1.78 RT (98.01% purity).

1- (4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazin-1-yl) Eth-1-one (Ex. 37)

To 1-cyclopropyl-5,6-difluoro-2- (6- (piperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] A stirred solution of imidazole (50 mg, 0.14 mmol) in CH ₂ Cl ₂ (1 mL) was added triethylamine (0.05 mL, 0.42 mmol) and acetamidine chloride (0.01 mL, 0.14 mmol). The reaction mixture was stirred at 0 ° C for 10 min. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1- (4- (5- (1-cyclopropyl-5, 6-difluoro-1H-benzo [d] imidazol-2-yl) pyrazin -3-yl) piperazin-1-yl) ethan- 1-one Ex. 37 (14 mg, 0.03 mmol, 25%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.20 (s, 1H), 7.57 (dd, J = 10.1, 7.2Hz, 1H), 7.49 (s, 1H), 7.42 (dd, J = 9.6, 6.9Hz, 1H), 3.94-3.89 (m, 2H), 3.84-3.78 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.64 (m, 2H), 3.64-3.59 (m, 1H), 2.18 ( s, 3H), 1.32-1.26 (m, 2H), 0.86-0.81 (m, 2H)

LC-MS: m / z 399.1 [M + H] ⁺ at 1.57 RT (93.31% purity).

HPLC: 92.89%.

[Example 38]

1-cyclopropyl-5,6-difluoro-2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyrazin-4-yl) -1 H -benzo [ d ] Imidazole (Ex. 38)

To 1-cyclopropyl-5,6-difluoro-2- (6- (piperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] A stirred solution of imidazole (50 mg, 0.14 mmol) in CH ₂ Cl ₂ (1 mL) was added triethylamine (0.05 mL, 0.42 mmol) and methanesulfonyl chloride (0.01 mL, 0.14 mmol). The reaction mixture was stirred for 10 min. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (6 as a pale yellow solid. - (4- (methylsulfonyl sulfo acyl) piperazin-1-yl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.38 (14mg, 0.03mmol, 25% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.22 (s, 1H), 7.57 (dd, J = 10.1, 7.2Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J = 9.6, 6.9Hz, 1H), 3.96-3.91 (m, 4H), 3.65-3.60 (m, 1H), 3.43-3.38 (m, 4H), 2.84 (s, 3H), 1.34-1.24 (m, 2H), 0.91-0.80 ( m, 2H)

LC-MS: m / z 435.1 [M + H] ⁺ at 2.09 RT (98.86% purity).

HPLC: 97.10%.

[Example 39]

4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (Ex.39)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 200 mg, 0.65 mmol) of a stirred solution in dimethyl sulfoxide (DMSO) (4 mL) was added piperazine-1-carboxylic acid tert-butyl ester (729 mg, 3.97 mmol). The reaction mixture was stirred at 130 ° C for 3 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain Ex. 39 (230 mg, 0.50 mmol, 77%) as a brown solid.

¹ H NMR (400MHz, CDCl ₃ ): δ 9.17 (s, 1H), 7.57 (dd, J = 10.0, 7.2Hz, 1H), 7.47 (s, 1H), 7.41 (dd, J = 9.7, 6.9Hz, 1H), 3.78-3.75 (m, 4H), 3.64-3.58 (m, 5H), 1.50 (s, 9H), 1.31-1.26 (m, 2H), 0.86-0.81 (m, 2H)

LC-MS: m / z 457.1 [M + H] ⁺ at 2.52 RT (97.87% purity).

HPLC: 95.78%.

[Examples 40 & 41]

6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyrazine-4-carboxamide

To a stirred solution of 6-chloropyridazine-4-carboxylic acid (100 mg, 0.64 mmol) in DMF (2 mL) at room temperature under an inert atmosphere, 4-amino-3- (ethylamino) benzyl was added. Nitrile Int-4 (104 mg, 0.64 mmol), HATU (369.9 mg, 0.97 mmol) and ethyldiisopropylamine (0.45 mL, 2.59 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with aqueous ammonium chloride (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyridazine- as a yellow solid 4-formamidine (90 mg, crude material).

LC-MS: m / z 300.9 [M] ⁺ at 2.07 RT (36.25% purity).

1-ethyl-2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.40)

Under an inert atmosphere, 6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyrazine-4-carboxamide (100 mg, 0.33 mmol) in CH _{2 was added} at 0 ° C. A stirred solution in Cl ₂ (1.6 mL) was added trifluoroacetic acid (0.4 mL). The reaction mixture was stirred at 0 ° C for 6 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was triturated with ether (2 x 10 mL) and n-pentane (2 x 10 mL) to give 1-ethyl-2- (6-methoxypyridazin-4-yl) -1H-benzene as an off-white solid. And [d] imidazole-6-carbonitrile Ex. 40 (25 mg, 0.09 mmol, 26%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.27 (d, J = 1.9Hz, 1H), 8.24 (s, 1H), 7.91 (dd, J = 8.4,0.6Hz, 1H), 7.68 (dd, J = 8.5, 1.4Hz, 1H), 7.59 (s, 1H), 4.53-4.49 (m, 2H), 4.22 (s, 3H), 1.48 (t, J = 7.3Hz, 3H)

LC-MS: m / z 279.8 [M + H] ⁺ at 2.15 RT (98.27% purity).

HPLC: 98.65%.

2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.17)

1-Ethyl-2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 40 (85 mg, 0.30 mmol) in phosphonium chloride The stirred solution (0.57 mL, 6.09 mmol) was placed under an inert atmosphere at room temperature. The reaction mixture was heated to 100 ° C for 2 h. After consuming the starting material (by TLC), the reaction mixture was basified with aqueous sodium carbonate (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was triturated with ether (2 x 5 mL) and n-pentane (2 x 5 mL) to give 2- (6-chloropyrazin-4-yl) -1-ethyl- 1H -benzene as a pale yellow slurry. [[ D ] imidazole-6-carbonitrile Ex. 17 (100 mg, crude), which was used in the next step without further purification.

1-ethyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 17 (130 mg, 0.46 mmol) To a stirred solution of 1,4-dioxane (3 mL) and water (0.5 mL) was added vinyl borate pinacol (70 mg, 0.46 mmol) and potassium carbonate (190 mg, 1.37 mmol). The reaction mixture was degassed under argon for 10 min. Was added _{Pd (dppf) Cl 2 (3.7mg} , 0.005mmol) at room temperature and to this mixture was degassed under argon Further 10min. The reaction mixture was heated to 80 ° C and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 1-ethyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (110 mg, Coarse material).

LC-MS: m / z 275.9 [M + H] ⁺ at 2.18 RT (78.16% purity).

1-ethyl-2- (6-ethylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.41)

To 1-ethyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (110 mg, 0.40 mmol) at room temperature under an inert atmosphere. To the stirred solution in EtOAc (5 mL) was added 10% Pd / C (50% wet, 20 mg) and triethylamine (0.005 mL, 0.04 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 2 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 1-ethyl-2- (6-ethylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile Ex as an off-white solid . 41 (4 mg, 14.44 mmol, 4%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.51 (d, J = 2.0Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 2.1Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.4 Hz, 1H), 4.55-4.50 (m, 2H), 3.21-3.15 (m, 2H), 1.53-1.45 (m, 6H)

LC-MS: m / z 277.9 [M + H] ⁺ at 2.12 RT (96.23% purity).

HPLC: 96.66%.

[Example 42]

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 42)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( 100mg, 0.33mmol) in CH stirring the ₂ Cl ₂ (5mL) was added (diethylamino) sulfur trifluoride (DAST) (0.09mL, 0.66mmol) . The reaction mixture was warmed to room temperature and stirred for 1 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20mL) and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (difluoromethyl) pyridazine- 4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 42 (40 mg, 0.12 mmol, 37%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.99 (s, 1H), 8.55 (s, 1H), 7.93-7.85 (m, 2H), 7.42 (t, J = 54.5Hz, 1H), 4.01- 3.97 (m, 1H), 1.25-1.13 (m, 2H), 0.84-0.72 (m, 2H)

LC-MS: m / z 323.3 [M + H] ⁺ at 3.53 RT (98.91% purity).

HPLC: 99.33%.

[Example 43]

2- (6-Cyclobutoxypyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 43)

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( A stirred solution of 50 mg, 0.16 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 16.3 mg, 0.46 mmol) in portions. The reaction mixture was stirred at 0 ° C for 10 min. Subsequently, cyclobutanol (141 mg, 0.20 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH ₂ Cl ₂ ) to obtain 2- (6-cyclobutoxypyrazin-4-yl) -1 as an off-white solid. -Cyclopropyl -5,6-difluoro-1H-benzo [d] imidazole Ex. 43 (45 mg, 0.13 mmol, 57%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.42 (s, 1H), 7.59 (dd, J = 10.1, 7.2Hz, 1H), 7.47 (s, 1H), 7.44-7.40 (m, 1H), 5.53- 5.48 (m, 1H), 3.62-3.57 (m, 1H), 2.67-2.50 (m, 2H), 2.31-2.08 (m, 2H), 1.99-1.83 (m, 1H), 1.78-1.73 (m, 1H ), 1.37-1.24 (m, 2H), 0.89-0.77 (m, 2H)

LC-MS: m / z 343 [M + H] ⁺ at 2.61 RT (95.30% purity).

HPLC: 95.28%.

[Example 44]

[Program]

1-cyclopropyl-2- (6- (4,4-difluoropiperidin-1-yl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole ( Ex.44)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100 mg, 0.32 mmol) in a stirred solution of DMSO (2 mL) was added 4,4-difluoropiperidine (59 mg, 0.49 mmol). The reaction mixture was heated to 120-130 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50-60% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (4,4-difluoro) as an off-white solid. Piperidin-1-yl) pyrazin -4-yl) -5,6-difluoro-1H-benzo [d] imidazole Ex. 44 (40 mg, 0.10 mmol, 32%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.09 (s, 1H), 7.82 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 3.99-3.92 (m, 4H), 3.86-3.83 (m, 1H), 2.19-2.00 (m, 4H), 1.27-1.19 (m, 2H), 0.87-0.76 (m, 2H)

LC-MS: m / z 392.1 [M + H] ⁺ at 2.98 RT (93.89% purity).

HPLC: 92.05%.

[Example 45]

6-methylpyrazine-4-carboxylic acid

To a stirred solution of 3-chloro-6-methylpyrazine-4-carboxylic acid 1 (500 mg, 2.90 mmol) in MeOH (50 mL) was added sodium hydroxide (395 mg, 9.80 mmol) at room temperature under an inert atmosphere. And 10% Pd / C (50% wet, 150 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and 6N HCl was added up to about pH 6 and concentrated under reduced pressure to obtain 6-methylpyrazine-4-carboxylic acid (410 mg, crude material) as a yellow liquid, which was used without further purification Used for the next step.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.24 (s, 1H), 7.69 (s, 1H), 2.62 (s, 3H)

N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-methylpyrazine-4-carboxamide

Compound 6 was added to a stirred solution of 6-chloro- N 2-cyclopropylpyridine-2,3-diamine Int-8 (400 mg, 2.18 mmol) in DMF (5 mL) at room temperature under an inert atmosphere. -Methylpyrazine-4-carboxylic acid (362 mg, 2.62 mmol), HATU (996 mg, 2.62 mmol) and ethyldiisopropylamine (1.6 mL, 8.75 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-formaldehyde as a black solid. Methylpyrazine-4-carboxamide (200 mg, 0.66 mmol, 30%), which was used in the next step without further purification.

LC-MS: m / z 303.9 [M + H] ⁺ at RT 2.06 (93.73% purity).

5-chloro-3-cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (Ex.45)

Under an inert atmosphere, N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-methylpyrazine-4-carboxamide (100 mg, 0.33 mmol) ) To a stirred solution in EtOH (2 mL) was added 6N HCl (3 mL). The reaction mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC by line to give 5-chloro-3-cyclopropyl-brown solid 2- (6-methyl-pyridazine-4-yl) -3 H - imidazo [4,5- b ] Pyridine Ex. 45 (12 mg, 0.04 mmol, 10%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.67 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 3.83-3.78 (m, 1H), 2.84 (s, 3H), 1.29-1.25 (m, 2H), 0.94-0.92 (m, 2H)

LC-MS: m / z 285.9 [M + H] ⁺ at 2.03 RT (98.73% purity).

HPLC: 95.65%.

[Example 46]

1-cyclopropyl-2- (6- (3,3-difluoropyrrolidin-1-yl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole ( Ex.46)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100 mg, 0.32 mmol) in a stirred solution of DMSO (2 mL) was added 3,3-difluoropyrrolidine hydrochloride (70 mg, 0.50 mmol) and triethylamine (0.06 mL, 0.49 mmol). The reaction mixture was heated to 130 ° C and stirred for 48 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give 1-cyclopropyl-2- (6- (3,3-difluoropyrrolidin-1-yl) pyridazin-4-yl) -5,6 as an off-white solid. -Difluoro - 1H -benzo [ d ] imidazole Ex. 46 (15 mg, 0.04 mmol, 12%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.10 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 7.49 (d, J = 1.8Hz, 1H), 4.03 (t, J = 12.9Hz, 2H), 3.90-3.77 (m, 3H), 2.69-2.54 (m, 2H), 1.30-1.22 (m, 2H), 0.86-0.80 (m, 2H)

LC-MS: m / z 378.1 [M + H] ⁺ at 2.80 RT (97.60% purity).

HPLC: 99.55%.

[Example 47]

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl -1-ol (Ex.47)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( 50 mg, 0.16 mmol) of a stirred solution in THF (1 mL) was added trimethyl (trifluoromethyl) silane (47 mg, 0.33 mmol). Cesium fluoride (76 mg, 0.50 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at room temperature for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with a 1 N HCl solution (5 mL) at 0 ° C and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1- (5- (1-cyclopropyl-5,6-difluoro-1) as a brown solid. H -Benzo [ d ] imidazol-2-yl) pyrazin -3-yl) -2,2,2-trifluoroethyl-1-ol Ex. 47 (10 mg, 0.03 mmol, 16%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.83 (s, 1H), 8.58 (s, 1H), 7.75-7.71 (m, 1H), 7.67-7.63 (m, 1H), 5.60-5.52 (m, 1H), 3.94-3.81 (m, 1H), 1.35-1.21 (m, 2H), 0.93-0.78 (m, 2H)

LC-MS: m / z 371 [M + H] ⁺ at 2.69 RT (95.24% purity).

HPLC: 95.69%.

[Example 48]

[Program]

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -N , N -dimethylpyrrolidine -3-amine (Ex. 48)

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 115 mg, 0.37 mmol) in a stirred solution of DMSO (2 mL) was added triethylamine (0.116 mL, 0.84 mmol) and 1- (3- (dimethylamino) -115-pyrrolidin-1-yl) -2 , 2,2-trifluoroethan-1-one (120 mg, 0.56 mmol). The reaction mixture was stirred at 90 ° C for 5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5-10% MeOH / CH ₂ Cl ₂ ) to obtain 1- (5- (1-cyclopropyl-5,6- Difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -N, N -dimethylpyrrolidin-3-amine Ex.48 (10mg, 0.02m mol, 7% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.01 (s, 1H), 7.72-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.44 (s, 1H), 3.96-3.93 (m, 1H), 3.86-3.81 (m, 2H), 3.62-3.55 (m, 1H), 3.45-3.37 (m, 1H), 3.09-2.99 (m, 1H), 2.38 (s, 6H), 2.08-1.95 ( m, 1H), 1.32-1.20 (m, 3H), 0.87-0.78 (m, 2H)

LC-MS: m / z 385.1 [M + H] ⁺ at 2.06 RT (97.17% purity).

HPLC: 98.58%.

[Example 49]

1-cyclopropyl-5,6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 49)

Pd (PPh ₃ ) ₂ Cl ₂ (11.5 mg, 0.01 mmol) and carbonic acid in 1,4-dimethoxyethane (DME): water (4: 1,1.25 mL) at room temperature Sodium (86.4 mg, 0.81 mmol) was flushed under argon for 5 min. At room temperature, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 (50 mg, 0.16 mmol ) And (4-fluorophenyl) boronic acid (25.1 mg, 0.17 mmol) were added to the reaction mixture. The reaction mixture was stirred in a sealed tube at 80 ° C for 12 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.49 (40mg, 0.10mmol, 48% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.75 (s, 1H), 8.68 (s, 1H), 8.32-8.18 (m, 2H), 7.76-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.35 (t, J = 8.8Hz, 2H), 3.98-3.93 (m, 1H), 1.32-1.25 (m, 2H), 0.90-0.84 (m, 2H)

LC-MS: m / z 367 [M + H] ⁺ at 2.58 RT (98.75% purity).

HPLC: 98.72%.

[Example 50]

1-cyclopropyl-5,6-difluoro-2- (6-((4-fluorophenyl) ethynyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.50 )

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100mg, 0.32mmol) in a stirred solution of N, N -dimethylacetamide (DMA) (3mL) was added 1-ethynyl-4-fluorobenzene (40mg, 0.32mmol) and potassium carbonate (90mg, 0.65 mmol). The reaction mixture was degassed with argon for 10 min. Pd ₂ (dba) ₃ (14.8 mg, 0.01 mmol) and X-phos (8 mg, 0.01 mmol) were added at room temperature and the mixture was degassed with argon for another 5 min. The reaction mixture was heated to 80 ° C and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-(( 4-fluorophenyl) ethynyl) pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.50 (50mg, 0.13mmol, 39% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.81 (s, 1H), 8.49 (s, 1H), 7.91-7.84 (m, 2H), 7.84-7.76 (m, 2H), 7.38 (t, J = 9.0Hz, 2H), 4.01-3.93 (m, 1H), 1.24-1.16 (m, 2H), 0.85-0.71 (m, 2H)

LC-MS: m / z 391.3 [M + H] ⁺ at 4.58 RT (97.94% purity).

HPLC: 96.14%.

[Example 51]

1-cyclopropyl-5,6-difluoro-2- (6- (prop-1-en-2-yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (120 mg, 0.40 mmol) in 1,4 -A stirred solution of dioxane (3.2 mL) and water (0.8 mL) was added to 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2 -Dioxolane (219 mg, 1.17 mmol) and sodium carbonate (164.6 mg, 1.56 mmol) and the mixture was flushed with argon at room temperature for 10 min. Pd (PPh ₃ ) ₄ (23 mg, 0.02 mmol) was added to the reaction mixture. The reaction mixture was heated at 110 ° C for 8 h. After consuming the starting material (by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Triturate the crude material with n-pentane (2 x 5 mL) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- (prop-1-en-2-yl) pyridazine as an off-white solid 4-yl) -1 H - benzo [d] imidazole (100 mg, crude), which was used without further purification in the next step.

LC-MS: m / z 313.1 [M + H] ⁺ at 2.38 RT (94.08% purity).

1-cyclopropyl-5,6-difluoro-2- (6-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.51)

To 1-cyclopropyl-5,6-difluoro-2- (6- (prop-1-en-2-yl) pyridazin-4-yl) -1 H -at room temperature under an inert atmosphere A stirred solution of benzo [ d ] imidazole (100 mg, 0.32 mmol) in ethyl acetate (5 mL) was added with triethylamine (0.04 mL), sodium hydroxide (25 mg, 0.64 mmol), and 10% Pd / C (50% wet , 30mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-pentane (2 x 2 mL) and ether (2 x 2 mL) to give 1-cyclopropyl-5,6-difluoro-2- (6-isopropylpyridazine- 4- yl) -1 H - benzo [d] imidazole Ex.51 (55mg, 0.17mmol, 55% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.63 (s, 1H), 8.22 (s, 1H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 1H), 3.91-3.86 (m, 1H), 3.49-3.31 (m, 1H), 1.47 (d, J = 7.0Hz, 6H), 1.31-1.20 (m, 2H), 0.86-0.73 (m, 2H)

LC-MS: m / z 315.1 [M + H] ⁺ at 2.31 RT (97.95% purity).

HPLC: 99.16%.

[Example 52]

N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) ethanesulfonamide (Ex .52)

To (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methylamine at room temperature under an inert atmosphere (140mg, 0.46mmol) in CH stirring the ₂ Cl ₂ (4mL) was added triethylamine (0.19mL, 0.79mmol) and ethane sulfonic acyl chloride (65.7mg, 0.51mmol). The reaction mixture was stirred at room temperature for 1 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give N-((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazine as a white solid -3-yl) methyl) ethanesulfonamide Ex.52 (18 mg, 0.04 mmol, 10%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.72 (s, 1H), 8.52 (s, 1H), 7.76-7.70 (m, 1H), 7.66-7.61 (m, 1H), 4.71 (s, 2H) , 3.88-3.82 (m, 1H), 3.24-3.19 (m, 2H), 1.43-1.33 (m, 5H), 0.86-0.79 (m, 2H)

LC-MS: m / z 394 [M + H] ⁺ at 2.32 RT (99.29% purity).

HPLC: 98.78%.

[Example 53]

1-cyclopropyl-5,6-difluoro-2- (6-((1,1,1-trifluoroprop-2-yl) oxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 53)

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( A stirred solution of 75 mg, 0.24 mmol) in DMF (2.25 mL) was added sodium hydride (60% in mineral oil, 24.5 mg, 0.61 mmol) in portions. The reaction mixture was stirred at 0 ° C for 10 min. Subsequently, 1,1,1-trifluoroprop-2-ol (34 mg, 0.30 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- ((1,1,1-trifluoroprop-2-yl) oxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 53 (60 mg, 0.15 mmol, 84%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.54 (s, 1H), 7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.45-7.41 (m, 1H), 6.15-6.04 (m, 1H ), 3.69-3.42 (m, 1H), 1.64 (d, J = 6.3Hz, 3H), 1.36-1.24 (m, 2H), 0.92-0.81 (m, 2H)

LC-MS: m / z 385.1 [M + H] ⁺ at 2.76 RT (97.88% purity).

HPLC: 97.83%.

[Example 54]

3-cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (Ex.54)

To 5-chloro-3-cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine Ex.45 (75mg, 0.26 mmol) in a stirred solution in DMF (0.8 mL) was added zinc cyanide (61.5 mg, 0.52 mmol) and Pd (PPh ₃ ) ₄ (30.3 mg, 0.02 mmol). The mixture was flushed with argon for 10 min and then heated to 170 ° C for 4.5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC system to yield an off-white solid by 3-cyclopropyl-2- (6-methyl-pyridazine-4-yl) -3 H - imidazo [4,5- b] pyridin-5 -Nitrile Ex. 54 (25 mg, 0.09 mmol, 35%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.75 (s, 1H), 8.19 (d, J = 8.2Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.2Hz, 1H), 3.70 -3.64 (m, 1H), 2.90 (s, 3H), 1.41-1.36 (m, 2H), 1.06-0.81 (m, 2H)

LC-MS: m / z 276.9 [M + H] ⁺ at 1.88 RT (98.98% purity).

HPLC: 95.03%.

[Example 55]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide

To a stirred solution of N 1-cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (300 mg, 1.63 mmol) in DMF (3 mL) at room temperature under an inert atmosphere Pyrazine-4-carboxylic acid (202 mg, 1.63 mmol), HATU (743 mg, 1.95 mmol) and ethyldiisopropylamine (1.1 mL, 6.52 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyridazin-4 as an off-white solid. -Formamidine (250 mg, crude), which was used in the next step without further purification.

LC-MS: m / z 291 [M + H] ⁺ at 2.34 RT (96.97% purity).

1-Cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 55)

Under an inert atmosphere, N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide (200 mg, 0.68 mmol) in EtOH (4 mL The stirred solution in) was added 6N HCl (2 mL). The reaction mixture was stirred at 70 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with n-pentane (2 x 5 mL) to give 1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -1 H -benzo [ d as an off-white solid ] Imidazole Ex. 55 (120 mg, 0.44 mmol, 64%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.81 (s, 1H), 9.41 (dd, J = 5.4, 1.3Hz, 1H), 8.33 (dd, J = 5.5, 2.3Hz, 1H), 7.4-7.69 (m, 1H), 7.65-7.61 (m, 1H), 3.87-3.84 (m, 1H), 1.30-1.24 (m, 2H), 0.88-0.73 (m, 2H)

LC-MS: m / z 272.9 [M + H] ⁺ at 2.21 RT (99.23% purity).

HPLC: 99.54%.

[Example 56]

1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -4- (trifluoromethyl) -1 H -benzo [ d ] imidazole (Ex. 56)

To 1-cyclopropyl-5,6-difluoro-2- ( dazin -4-yl) -1 H -benzo [ d ] imidazole Ex. 55 (100 mg, 0.36 mmol) in a stirred solution in DMSO (1.5 mL) was added zinc triflate (243 mg, 0.73 mmol). To this was added TBHP (141 mg, 1.10 mmol) at 0 ° C. The reaction mixture was stirred at 50 ° C for 16 h. After consumption of the starting material (by TLC), the reaction mixture (20mL) and basified with saturated sodium bicarbonate solution and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give 1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -4- (trifluoromethyl) -1 H -as an off-white solid. Benzo [ d ] imidazole Ex. 56 (19 mg, 0.05 mmol, 15%).

¹ H NMR (500MHz, CD ₃ OD): δ 9.85 (s, 1H), 9.44 (dd, J = 5.2, 1.2Hz, 1H), 8.38 (dd, J = 5.2, 2.3Hz, 1H), 8.06 (dd , J = 9.3, 7.0Hz, 1H), 3.92-3.86 (m, 1H), 1.38-1.20 (m, 2H), 0.89-0.83 (m, 2H)

LC-MS: m / z 340.9 [M + H] ⁺ at 2.75 RT (91.67% purity)

HPLC: 91.79%

[Example 57]

[Program]

1-cyclopropyl-2- (6- (2,2-difluoropropoxy) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.57 )

To 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 ( A stirred solution of 50 mg, 0.16 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 16.2 mg, 0.40 mmol) in portions and the mixture was stirred for 5 min. 2,2-Difluoroprop-1-ol (18.8 mg, 0.19 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with CH ₂ Cl ₂ : n-pentane (5:95, 10 mL) to give 1-cyclopropyl-2- (6- (2,2-difluoropropoxy) pyridazine as an off-white solid. -4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 57 (45 mg, 0.12 mmol, 82%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.53 (s, 1H), 7.65 (d, 1H), 7.60 (dd, J = 10.0, 7.3Hz, 1H), 7.43 (dd, J = 9.7, 6.9Hz, 1H), 4.80 (t, J = 12.1Hz, 2H), 3.67-3.58 (m, 1H), 1.80 (t, J = 18.6Hz, 3H), 1.39-1.27 (m, 2H), 0.92-0.76 (m , 2H)

LC-MS: m / z 367 [M + H] ⁺ at 3.08 RT (96.40% purity)

HPLC: 94.40%

[Example 58]

1-cyclopropyl-5,6-difluoro-2- (5-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 58)

To 1-cyclopropyl-5,6-difluoro-2- ( dazin -4-yl) -1 H -benzo [ d ] imidazole Ex. 55 (100 mg, 0.37 mmol) In a stirred solution of DMSO (1 mL) was added zinc isopropylsulfinate (205 mg, 0.73 mmol). Subsequently, a third butyl hydroperoxide (70% in water, 142 mg, 1.1 mmol) was added at 0 ° C. The reaction mixture was gradually warmed to room temperature and then heated to 50 ° C for 16 h. After consumption of the starting material (by TLC), the reaction mixture was basified and extracted with EtOAc (2 x 30mL) with saturated NaHCO ₃ solution (pH about 8). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane), followed by trituration with n-pentane (2 x 4 mL) and drying under vacuum to give 1 as an off-white solid. -Cyclopropyl -5,6-difluoro-2- (5-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 58 (15 mg, 0.05 mmol, 13%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.48 (d, J = 0.8Hz, 1H), 9.31 (d, J = 1.0Hz, 1H), 7.71 (dd, J = 10.1,7.1Hz, 1H), 7.61 (dd, J = 10.5,7.3Hz, 1H), 3.62-3.56 (m, 1H), 3.27-3.20 (m, 1H), 1.33 (d, J = 7.0Hz, 6H), 1.08-1.03 (m, 2H), 0.73-0.68 (m, 2H)

LC-MS: m / z 315.0 [M + H] ⁺ at 2.70 RT (95.37% purity)

HPLC: 92.84%

[Example 59]

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.59)

To 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (70mg, 0.22mmol) in a sealed tube To a stirred solution in toluene / water (3: 1,2 mL) was added cyclopropylboronic acid (24 mg, 0.27 mmol) and cesium carbonate (186 mg, 0.57 mmol) and the mixture was rinsed under argon for 10 min. Pd (dppf) Cl ₂ (18.6 mg, 0.02 mmol) was added to the reaction mixture, and further degassed for 5 min. The reaction was heated to 110 ° C for 16 h and then cooled. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6-cyclopropylpyridazine-4- as a pale yellow solid. ) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 59 (8 mg, 0.02 mmol, 11%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.57 (s, 1H), 7.81 (s, 1H), 7.59 (dd, J = 10.2, 7.3Hz, 1H), 7.43 (dd, J = 9.7, 7.0Hz, 1H), 3.67-3.60 (m, 1H), 2.32-2.24 (m, 1H), 1.35-1.27 (m, 4H), 1.25-1.19 (m, 2H), 0.86-0.80 (m, 2H)

LC-MS: m / z 313.1 [M + H] ⁺ at 2.22 RT (93.72% purity)

HPLC: 96.07%

[Example 60]

6-chloro- N- (2- (cyclopropylamino) -6-methoxypyridin-3-yl) pyrazine-4-carboxamide

To a stirred solution of 6-chloropyridazine-4-carboxylic acid (500 mg, 3.16 mmol) in DMF (10 mL) at 0 ° C was added N ² -cyclopropyl-6-methoxypyridine-2 , 3-diamine Int-9 (566 mg, 3.16 mmol), HATU (1.8 g, 4.74 mmol) and diisopropylethylamine (2.19 mL, 12.64 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to obtain 6-chloro- N- (2- (cyclopropylamino) -6) as an off-white solid. -Methoxypyridin-3-yl) pyridazin-4-methylamidine (225 mg, 0.70 mmol, 22%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.91 (s, 1H), 9.62 (s, 1H), 8.35 (s, 1H), 7.33 (d, J = 8.2Hz, 1H), 6.50 (d, J = 2.4Hz, 1H), 6.00 (d, J = 8.0Hz, 1H), 3.82 (s, 3H), 2.73-2.70 (m, 1H), 0.73-0.64 (m, 2H), 0.52-0.40 (m , 2H)

2- (6-chloropyrazin-4-yl) -3-cyclopropyl-5-methoxy-3 H -imidazo [4,5- b ] pyridine (Ex.60)

To 0-chloro- N- (2- (cyclopropylamino) -6-methoxypyridin-3-yl) pyrazine-4-carboxamide (150 mg, 0.47 A stirred solution of mmol) in EtOH (3.5 mL) was added 6 N HCl (2 mL). The reaction mixture was stirred at 80 ° C for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 60-70% EtOAc / hexane) to give 2- (6-chloropyrazin-4-yl) -3-cyclopropane as a brown solid. Methyl-5-methoxy- 3H -imidazo [4,5- b ] pyridine Ex. 60 (35 mg, 0.11 mmol, 22%).

¹ H NMR (400MHz, CD ₃ OD): δ 8.28 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.3Hz, 1H), 6.03 (d, J = 8.3Hz, 1H), 3.90 (s, 3H), 2.79-2.74 (m, 1H), 0.77-0.68 (m, 2H), 0.53-0.47 (m, 2H)

LC-MS: m / z 302.1 [M + H] ⁺ at 1.85 RT (95.67% purity)

HPLC: 94.24%

[Example 61]

1-cyclopropyl-5,6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 61)

To 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (70mg, 0.22mmol) in a sealed tube To a stirred solution in DME / EtOH (2: 1, 0.9 mL) was added (4-fluoro-2-methylphenyl) boronic acid (42 mg, 0.27 mmol) and sodium carbonate (72.5 mg, 0.68 mmol) and the mixture was mixed in Rinse under argon for 10 min. Trans-dichlorobis (triphenylphosphine) -II was added to the reaction mixture and the reaction mixture was stirred at 80 ° C. for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6- (4 - fluoro-2-methylphenyl) pyridazin-4-yl) -1 H - benzo [d] imidazole Ex.61 (45mg, 0.11mmol, 51% ).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.81 (s, 1H), 8.14 (s, 1H), 7.60 (dd, J = 10.1, 7.2Hz, 1H), 7.49 (dd, J = 8.34, 5.83Hz, 1H), 7.44 (dd, J = 9.6, 6.9Hz, 1H), 7.11-7.03 (m, 2H), 3.71-3.63 (m, 1H), 2.46 (s, 3H), 1.37-1.30 (m, 2H) , 0.93-0.87 (m, 2H)

LC-MS: m / z 381.1 [M + H] ⁺ at 2.60 RT (97.81% purity)

HPLC: 96.11%

[Example 62]

[Program]

1-cyclopropyl-2- (6- (2,4-difluorophenyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.62)

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (70 mg, 0.22 mmol) in DME: EtOH (2: 1,0.9 mL) was added to the stirred solution (2,4-difluorophenyl) boronic acid (43 mg, 0.27 mmol) and sodium carbonate (75.5 mg, 0.68 mmol) and the mixture was rinsed under argon for 10 min. Trans-dichlorobis (triphenylphosphine) -II (8 mg, 0.01 mmol) was added to the reaction mixture and the reaction mixture was stirred in a sealed tube at 80 ° C. for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (2,4-difluorophenyl) as an off-white solid. ) Dazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 62 (45 mg, 0.11 mmol, 51%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.79 (s, 1H), 8.51 (s, 1H), 8.36-8.29 (m, 1H), 7.62 (dd, J = 10.2, 7.3Hz, 1H), 7.44 ( dd, J = 9.6, 7.0Hz, 1H), 7.16-7.10 (m, 1H), 7.03-6.97 (m, 1H), 3.71-3.64 (m, 1H), 1.38-1.32 (m, 2H), 0.92- 0.87 (m, 2H)

LC-MS: m / z 385.1 [M + H] ⁺ at 2.61 RT (96.45% purity)

HPLC: 96.95%

[Example 63]

1-cyclopropyl-2- (6- (3,4-difluorophenyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 63)

To 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex.22 (70 mg, 0.22 mmol) in a sealed tube To a stirred solution in DME / EtOH (2: 1, 0.9 mL) was added (3,4-difluorophenyl) boric acid (43 mg, 0.27 mmol) and sodium carbonate (75.5 mg, 0.68 mmol) and the mixture was under argon Rinse for 10 minutes. Trans-dichlorobis (triphenylphosphine) -II was added to the reaction mixture and the reaction mixture was stirred at 80 ° C. for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (3,4-difluorophenyl) as an off-white solid. ) Dazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 63 (45 mg, 0.11 mmol, 51%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.79 (s, 1H), 8.43 (s, 1H), 8.14-8.09 (m, 1H), 7.96-7.90 (m, 1H), 7.62 (dd, J = 10.0 , 7.3Hz, 1H), 7.46 (dd, J = 9.5, 6.9Hz, 1H), 7.36 (dd, J = 17.9, 8.7Hz, 1H), 3.79-3.66 (m, 1H), 1.39-1.29 (m, 2H), 0.93-0.82 (m, 2H)

LC-MS: m / z 385 [M + H] ⁺ at 2.62 RT (98.32% purity)

HPLC: 98.68%

[Example 64 & Example 70]

1-cyclopropyl-2- (6- (1-ethoxyvinyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole

To 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 (200 mg, 0.65 mmol) at room temperature To a stirred solution in DMF (4 mL) was added tributyl (1-ethoxyvinyl) stannane (0.26 mL, 0.78 mmol) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (53 mg, 0.06 mmol) and The mixture was degassed under argon for 10 min. The reaction mixture was stirred at 100 ° C for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (1-ethoxyethylene) as a light brown semi-solid Yl) pyridazin-4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole (180 mg, 0.52 mmol, 81%).

LC-MS: m / z 343.1 [M + H] ⁺ at 3.10 RT (81.31% purity)

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one (Ex.64)

At room temperature, 1-cyclopropyl-2- (6- (1-ethoxyvinyl) pyrazin-4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole (180 mg, 0.52 mmol) in a stirred solution of acetone (3 mL) was added 2.5 N HCl (2 mL). The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (40 mL) and washed with saturated sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazole-2 as a light brown solid. -Yl ) pyridazin-3-yl) ethan- 1-one Ex. 64 (110 mg, 0.35 mmol, 69%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 10.01 (d, J = 2.3Hz, 1H), 8.62 (d, J = 2.3Hz, 1H), 7.91-7.82 (m, 2H), 3.99-3.94 ( m, 1H), 2.85 (s, 3H), 1.19-1.14 (m, 2H), 0.79-0.75 (m, 2H)

LC-MS: m / z 315.0 [M + H] ⁺ at 2.65 RT (95.59% purity)

HPLC: 93.77%

1-cyclopropyl-2- (6- (1,1-difluoroethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 70)

Under an inert atmosphere, 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one A solution of Ex. 70 (110 mg, 0.35 mmol) in DAST (3 mL) was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane), which was further purified by preparative HPLC to give 1-cyclopropyl-2- (6- ( 1,1-difluoroethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 70 (45 mg, 0.13 mmol, 41%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.98 (d, J = 2.1 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 7.94-7.85 (m, 2H), 4.02-3.97 ( m, 1H), 2.22 (t, J = 19.4Hz, 3H), 1.21-1.14 (m, 2H), 0.83-0.77 (m, 2H)

LC-MS: m / z 337.0 [M + H] ⁺ at 2.99 RT (99.31% purity)

HPLC: 99.50%

[Example 65]

6-chloro- N- (2- (ethylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide

To a stirred solution of N ¹ -ethyl-4,5-difluorobenzene-1,2-diamine Int-10 (500 mg, 2.9 mmol) in EtOAc (15 mL) at 0 ° C under an inert atmosphere. 6-chloropyrazine-4-carboxylic acid (505 mg, 3.19 mmol), triethylamine (0.8 mL, 5.81 mmol), and propylphosphonic anhydride (50% in EtOAc, 4.5 mL, 7.26 mmol). The reaction mixture was stirred at room temperature for 5 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with water (70 mL), brine (70 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 15% EtOAc / hexane) to give 6-chloro- N- (2- (ethylamino) -4,5- as a yellow solid. Difluorophenyl) pyridazine-4-carboxamide (500 mg, 1.60 mmol, 55%).

¹ H NMR (400MHz, CDCl ₃ ): δ 10.1 (brs, 1H), 9.65 (s, 1H), 8.39 (s, 1H), 7.3 (dd, J = 11.7,8.1Hz, 1H), 6.69 (dd, J = 12.1, 7.9Hz, 1H), 5.5 (brs, 1H), 3.12-3.02 (m, 2H), 1.17 (t, J = 7.2Hz, 3H)

LC-MS: m / z 312.9 [M + H] ⁺ at 2.69 RT (96.47% purity)

2- (6-chloropyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.65)

Under an inert atmosphere, 6-chloro-N- (2- (ethylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide (400 mg, 1.28 mmol) was added at room temperature to To the stirred solution in ethanol (4 mL) was added 6N HCl (6 mL). The reaction mixture was stirred at 50 ° C for 15 min. After consuming the starting material (by TLC), the reaction mixture was poured into a saturated sodium bicarbonate solution (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material (100 mg) was purified by preparative HPLC to give 2- (6-chloropyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d as an off-white solid [ d ] Imidazole Ex. 65 (30 mg, 0.10 mmol, 29%).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.59 (d, J = 1.9Hz, 1H), 8.20 (d, J = 1.9Hz, 1H), 7.73 (dd, J = 10.2, 7.0Hz, 1H), 7.65 (dd, J = 10.4,7.3Hz, 1H), 4.46 (q, J = 7.3Hz, 2H), 1.48 (t, J = 7.3Hz, 3H)

LC-MS: m / z 294.9 [M + H] ⁺ at 2.58 RT (98.60% purity)

HPLC: 99.85%

[Example 66]

1-cyclopropyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

In a sealed tube, add 2- (6-chloropyridazin-4-yl) -1-cyclopropyl- 1H -benzo [ d ] imidazole-6-carbonitrile Ex.34 (200mg, 0.67 mmol) A stirred solution of 1,4-dioxane (5 mL) and water (1.5 mL) was added pinacol vinyl borate (313 mg, 2.03 mmol) and potassium carbonate (374 mg, 2.71 mmol). The reaction mixture was degassed under argon for 10 min. To this was added Pd (dppf) Cl _2. CH ₂ Cl ₂ (5.3 mg, 0.006 mmol) at room temperature and the mixture was further degassed under argon for 10 min. The reaction mixture was heated to 100 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1-cyclopropyl-2- (6-vinyl taba) as a brown viscous slurry. oxazin-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile (200mg). The crude material was used in the next step without further purification.

LC-MS: m / z 288 [M + H] ⁺ at 2.27 RT (73.7% purity)

1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

To 1-cyclopropyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (200 mg, crude material at 0 ° C in an inert atmosphere) ) To a stirred solution of a mixture of third butanol (0.5 mL), acetone (0.5 mL), and water (0.5 mL) was added sodium periodate (29.68 mg, 0.13 mmol), followed by osmium tetroxide (0.1 M In toluene, 4 mL). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1 H -benzene as an orange solid. And [ d ] imidazole-6-carbonitrile (200 mg, crude material). The crude material was used in the next step without further purification.

LC-MS: m / z 308.1 [M + H ₂ O] ⁺ at 1.78 RT (8.32% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.66)

To 1-cyclopropyl-2- (6-methylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (200 mg, crude Substance) A stirred solution in CH ₂ Cl ₂ (10 mL) was added DAST (223 mg, 1.38 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20mL) and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane), which was further purified by preparative HPLC to give 1-cyclopropyl-2- (6- ( difluoromethyl) pyridazin-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile Ex.66 (15mg, 0.05mmol, 7% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.99 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 7.93 (dd, J = 8.4, 0.6Hz, 1H), 7.68 (dd , J = 8.4, 1.5Hz, 1H), 7.19 (t, J = 51.1Hz, 1H), 4.00-3.94 (m, 1H), 1.35-1.30 (m, 2H), 0.91-0.86 (m, 2H)

LC-MS: m / z 312 [M + H] ⁺ at 2.52 RT (98.91% purity)

HPLC: 99.83%

[Example 67]

[Program]

1-ethyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole

In a sealed tube, add 2- (6-chloropyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 65 (400 mg , Crude substance) To a stirred solution of 1,4-dioxane (12 mL) and water (4 mL) were added vinyl borate pinacol ester (419 mg, 2.72 mmol) and potassium carbonate (563 mg, 4.08 mmol). The reaction mixture was degassed under argon for 20 min. To this was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (11 mg, 0.013 mmol) at room temperature and the mixture was further degassed under argon for 10 min. The reaction mixture was heated to 80 ° C and stirred for 5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-ethyl-5,6-difluoro-2- (6-ethylene as an off-white solid. pyridazin-4-yl) -1 H - benzo [d] imidazole (100mg, crude material).

¹ H NMR (500 MHz, DMSO- d ₆ ) : δ 9.52 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.02 (dd, J = 10.4, 7.5 Hz, 1H) , 7.87 (dd, J = 11.0, 7.5Hz, 1H), 7.14 (dd, J =, 18.0, 11.0Hz, 1H), 6.54 (d, J = 17.4Hz, 1H), 5.82 (d, J = 11.6Hz , 1H), 4.45 (q, J = 7.5Hz, 2H), 1.34 (t, J = 7.2Hz, 3H)

LC-MS: m / z 287 [M + H] ⁺ at 2.47 RT (96.16% purity)

5- (1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde

To 1-ethyl-5,6-difluoro-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (100 mg, crude material) in acetone at 0 ° C: ^t BuOH: A stirred solution in water (1: 1: 1,6 mL) was added sodium periodate (149 mg, 0.69 mmol) and osmium tetroxide (1% in toluene, 2 mL). The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 5- (1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole-2 as a brown solid. -Dalmatazine-3-carbaldehyde (100 mg, crude material). This crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 10.37 (s, 1H), 9.88 (d, J = 2.3Hz, 1H), 8.39 (d, J = 2.3Hz, 1H), 8.04 (dd, J = 10.7, 7.2Hz, 1H), 7.90 (dd, J = 10.4, 7.5Hz, 1H), 4.46 (q, J = 7.3Hz, 2H), 1.37 (t, J = 7.2Hz, 3H)

LC-MS: m / z 289 [M + H] ⁺ at 1.87 RT (70.81% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.67)

To 5- (1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-ylpyridazin-3-carboxaldehyde (100 mg, crude substance) at 0 ° C under an inert atmosphere. DAST (0.09 mL, 0.69 mmol) was added to the stirred solution in CH ₂ Cl ₂ (8 mL). The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was ice-cooled It was quenched with water (30 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Crude The material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyrazin-4-yl) -1- as an off-white solid. Ethyl-5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 67 (30 mg, 0.09 mmol, 28%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.83 (d, J = 2.1Hz, 1H), 8.35 (d, J = 2.1Hz, 1H), 8.04 (dd, J = 10.8, 7.3Hz, 1H) , 7.89 (dd, J = 10.9, 7.5 Hz, 1H), 7.56-7.24 (m, 1H), 4.46 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H)

LC-MS: m / z 311.0 [M + H] ⁺ at 2.69 RT (98.69% purity)

HPLC: 98.72%

[Example 68 & Example 69]

6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyrazine-4-carboxamide

To a stirred solution of 4-amino-3- (ethylamino) benzonitrile Int-4 (200 mg, 1.24 mmol) in EtOAc (10 mL) at 0 ° C under an inert atmosphere, 6-chloropyrazine was added. 4-carboxylic acid (210 mg, 1.32 mmol), triethylamine (0.34 mL, 2.48 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.97 mL, 3.10 mmol). The reaction mixture was stirred at room temperature for 5 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 6-chloro- N- (4-cyano-2- (ethylamino)) as a yellow solid. Phenyl) pyrazine-4-carboxamide (250 mg, 0.83 mmol, 67%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.23 (brs, 1H), 9.65 (d, J = 1.2Hz, 1H), 8.39 (s, 1H), 7.40 (d, J = 8.1Hz, 1H) , 7.06-6.99 (m, 2H), 5.77 (br s, 1H), 3.20-3.15 (m, 2H), 1.17 (t, J = 7.0Hz, 3H)

2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex. 68)

Under an inert atmosphere, 6-chloro- N- (4-cyano-2- (ethylamino) phenyl) pyrazine-4-carboxamide (50 mg, 0.16 mmol) in CH _{2 was added} at 0 ° C. A stirred solution in Cl ₂ (2 mL) was added trifluoroacetic acid (0.2 mL). The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was quenched with a saturated sodium bicarbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 2- (6-chloropyrazin-4-yl) -1-ethyl-1 as an off-white solid. H -benzo [ d ] imidazole-6-carbonitrile Ex. 68 (35 mg, 0.12 mmol, 74%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.70 (d, J = 1.9Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 1.9Hz, 1H), 7.96 (dd, J = 8.4, 0.5Hz, 1H), 7.72 (dd, J = 8.5, 1.4Hz, 1H), 4.52 (q, J = 7.3Hz, 2H), 1.37 (t, J = 7.2Hz, 3H)

LC-MS: m / z 284 [M + H] ⁺ at 2.34 RT (97.52% purity)

HPLC: 97.70%

1-ethyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [d] imidazole-6-carbonitrile

To 2- (6-chloropyrazin-4-yl) -1-ethyl- 1H -benzo [ d ] imidazole-6-carbonitrile Ex. 68 (170 mg, 0.60 mmol) at 1, A stirred solution of a mixture of 4-dioxane (6 mL) and water (2 mL) was added vinyl borate pinacol ester (185 mg, 1.20 mmol) and potassium carbonate (248.69 mg, 1.80 mmol). The reaction mixture was degassed under argon for 20 min. To this was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (4.9 mg, 0.06 mmol) at room temperature and the reaction mixture was heated to 80 ° C. and stirred for 5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 1-2% MeOH / CH ₂ Cl ₂ ) to obtain 1-ethyl-2- (6-vinylpyridazine-4 as an off-white solid. - yl) -1 H - benzo [d] imidazole-6-carbonitrile (100mg, 0.36mmol, 61%) .

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.56 (d, J = 2.1Hz, 1H), 8.50-8.48 (m, 1H), 8.32 (d, J = 2.1Hz, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.72 (dd, J = 8.4,1.5Hz, 1H), 7.16 (dd, J = 17.8,11.0Hz, 1H), 6.56 (dd, J = 17.7,0.6Hz, 1H), 5.84 (d, J = 11.7Hz, 1H), 4.51 (q, J = 7.2Hz, 2H), 1.37 (t, J = 7.2Hz, 3H)

LC-MS: m / z 276.1 [M + H] ⁺ at 2.23 RT (95.18% purity)

1-ethyl-2- (6-methylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

To 1-ethyl-2- (6-vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (100 mg, 0.36 mmol) at 0 ° C under an inert atmosphere. To a stirred solution in acetone: ^t BuOH: water (1: 1: 1,6 mL) was added sodium periodate (154.9 mg, 0.72 mmol) and osmium tetraoxide (1% in toluene, 2 mL). The reaction mixture was stirred at room temperature for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 1-ethyl-2- (6-methylpyridazin-4-yl) -1 H -benzo as a viscous slurry. [ d ] Imidazole-6-carbonitrile (100 mg, crude material). The crude material was used in the next step without further purification.

LC-MS: m / z 278.1 [M + H] ⁺ at 1.65 RT (43.82% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.69)

To 1-ethyl-2- (6-methylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (100 mg, crude material at 0 ° C under an inert atmosphere) ) To a stirred solution in CH ₂ Cl ₂ (4 mL) was added DAST (0.09, 0.72 mmol). The reaction mixture was warmed to room temperature and stirred for 5 h. After consuming the starting material (by TLC), the reaction mixture was poured into ice-cold water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl) -1 as an off-white solid. -Ethyl- 1H -benzo [ d ] imidazole-6-carbonitrile Ex. 69 (30 mg, 0.10 mmol).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.81 (d, J = 2.0Hz, 1H), 8.42 (d, J = 2.0Hz, 1H), 8.28 (dd, J = 1.4,0.8Hz, 1H), 7.94 (dd, J = 8.4,0.6Hz, 1H), 7.69 (dd, J = 8.4,1.5Hz, 1H), 7.13 (t, J = 54.6Hz, 1H), 4.54 (q, J = 7.3Hz, 2H ), 1.52 (t, J = 7.3Hz, 3H)

LC-MS: m / z 300.0 [M + H] ⁺ at 2.41 RT (99.41% purity)

HPLC: 99.68%

[Example 71]

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl 1-ol

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( 400 mg, 1.33 mmol) in a stirred solution of DME (5 mL) was added cesium fluoride (202.6 mg, 1.33 mmol) and the mixture was stirred for 15 min. The _{TMS-CF 3 (284mg, 1.99mmol} ) was added to the reaction mixture at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with a 1 N HCl solution (20 mL), basified with a saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1- (5- (1-cyclopropyl-5,6-difluoro-1) as an off-white solid. H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2,2-trifluoroethan-1-ol (160 mg, 0.43 mmol, 32%).

¹ H NMR (500MHz, CD ₃ OD) : δ 9.84 (d, J = 2.3Hz, 1H), 8.58 (d, J = 1.7Hz, 1H), 7.73 (dd, J = 9.9, 7.0Hz, 1H), 7.65 (dd, J = 10.4,7.5Hz, 1H), 5.55 (q, J = 6.8Hz, 1H), 4.57 (s, 1H), 3.92-3.86 (m, 1H), 1.29-1.20 (m, 2H) , 0.88-0.78 (m, 2H)

LC-MS: m / z 371.1 [M + H] ⁺ at 2.76 RT (75.32% purity)

O- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazol-2-yl) pyrazin-3-yl) -2,2,2- S -methyl trifluoroethyl) dithiocarbonate

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 ° C under an inert atmosphere. A stirred solution of -2,2,2-trifluoroethyl-1-ol (100 mg, 0.27 mmol) in THF (5 mL) was added sodium hydride (60% in mineral oil, 21.6 mg, 0.54 mmol) in portions and the The mixture was stirred for 30 min. Carbon disulfide (41 mg, 0.54 mmol) was added to the reaction mixture at 0 ° C and stirred for 30 min, followed by methyl iodide (76 mg, 0.54 mmol) at 0 ° C and stirring was continued for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give O- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H- Benzo [ d ] imidazol-2-yl) pyridazin-3-yl) -2,2,2-trifluoroethyl) dithiocarbonate (100 mg). The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.88 (d, J = 2.3Hz, 1H), 8.56 (d, J = 1.7Hz, 1H), 7.92 (dd, J = 11.0, 7.5Hz, 1H) , 7.86 (dd, J = 10.4, 7.5 Hz, 1H), 7.52 (q, J = 6.8 Hz, 1H), 3.95-3.88 (m, 1H), 2.67 (s, 3H), 1.20-1.15 (m, 2H ), 0.79-0.73 (m, 2H)

LC-MS: m / z 461.1 [M + H] ⁺ at 3.63 RT (77.86% purity)

1-cyclopropyl-5,6-difluoro-2- (6- (2,2,2-trifluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 71)

O- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazine- 3-yl) -2,2,2-trifluoroethyl) dithiocarbonate (100 mg, 0.21 mmol) in a stirred solution of toluene (5 mL) was added AIBN (5.3 mg, 0.032 mmol) and tributyltin Alkane (95 mg, 0.32 mmol). The reaction mixture was heated to 60 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane), which was further purified by preparative HPLC to give 1-cyclopropyl-5,6-difluoro as an off-white solid. 2- (6- (2,2,2-trifluoroethyl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.71 (15mg, 0.04mmol, 19% ).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.84 (d, J = 2.0Hz, 1H), 8.16 (d, J = 1.6Hz, 1H), 7.61 (dd, J = 10.0,7.3Hz, 1H), 7.44 (dd, J = 9.5, 6.9Hz, 1H), 3.99 (q, J = 10.5Hz, 2H), 3.68-3.62 (m, 1H), 1.36-1.29 (m, 2H), 0.88-0.83 (m, 2H )

LC-MS: m / z 355.1 [M + H] ⁺ at 2.86 RT (98.85% purity)

HPLC : 99.79%

[Example 72]

2- (6-cyclopropylpyridazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.72)

In a sealed tube, give 2- (6-chloropyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 65 (150 mg, 0.51 mmol) to A stirred solution in toluene / water (3: 1, 12 mL) was added cyclopropylboronic acid (52.6 mg, 0.61 mmol) and cesium carbonate (416 mg, 1.27 mmol) and rinsed under argon for 20 min. Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (4 mg, 0.005 mmol) was added to the reaction mixture and rinsed again under argon at room temperature for 5 min. The reaction mixture was stirred at 100 ° C for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 2- (6-cyclopropylpyridazin-4-yl) -1-ethyl as an off-white solid. -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 72 (40 mg, 0.133 mmol, 26%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.35 (d, J = 2.0Hz, 1H), 7.85 (d, J = 2.1Hz, 1H), 7.71 (dd, J = 10.3,7.0Hz, 1H), 7.63 (dd, J = 10.4,7.3Hz, 1H), 4.43 (q, J = 7.3Hz, 2H), 2.44-2.36 (m, 1H), 1.46 (t, J = 7.2Hz, 3H), 1.30-1.24 (m, 4H)

LC-MS: m / z 301.0 [M + H] ⁺ at 2.58 RT (99.14% purity)

HPLC : 99.64%

[Example 73 & Example 76]

6-chloropyrazine-4-carboxylic acid methyl ester

To a stirred solution of 6-chloropyrazine-4-carboxylic acid (1.5 g, 9.49 mmol) in CH ₂ Cl ₂ (30 mL) under argon was added diazomethane in diethyl ether (by adding N -nitrosomethylurea (3 g) was added to a mixture of 50% KOH solution (25 mL) and diethyl ether (50 mL); warmed to RT and stirred for 30 min to prepare freshly). After consumption of the starting material (by TLC), the reaction mixture was filtered through diatomaceous earth and the pad was washed with CH ₂ Cl ₂ (30mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to obtain 6-chloropyrazine-4-carboxylic acid ester (1.4 g, 8.13 mmol, 86%) as an off-white solid. ).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.58 (d, J = 1.6Hz, 1H), 8.03 (d, J = 1.8Hz, 1H), 4.04 (s, 3H)

6-vinylpyrazine-4-carboxylic acid methyl ester

To a stirred solution of methyl 6-chloropyrazine-4-carboxylate (1.4 g, 8.13 mmol) in 1,2-dimethoxyethane (20 mL) in a sealed tube at room temperature under an inert atmosphere. Potassium carbonate (3.36 g, 24.39 mmol) and pinacol vinyl borate (2.56 mL, 16.2 mmol) were added. The reaction mixture was degassed under argon for 5-10 min. Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (66 mg, 0.08 mmol) was added to the reaction mixture at room temperature and degassed under argon for 5-10 min. The reaction mixture was heated to 80-90 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with EtOAc (50 mL), filtered through a celite pad and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give methyl 6-vinylpyrazine-4-carboxylate (1.3 g, 7.92 mmol) as an off-white solid. , 97%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.51 (d, J = 2.0Hz, 1H), 8.08 (d, J = 2.0Hz, 1H), 7.14 (dd, J = 17.8, 11.0Hz, 1H), 6.38 (d, J = 17.7Hz, 1H), 5.80 (d, J = 11.0Hz, 1H), 4.03 (s, 3H)

6-vinylpyrazine-4-carboxylic acid

To a stirred solution of methyl 6-vinylpyrazine-4-carboxylic acid methyl ester (1.4 g, 8.53 mmol) in THF: water (1: 2, 12.75 mL) at 0 ° C was added lithium hydroxide (716 mg, 17.07 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The residue was acidified (pH ca. 1-2) using concentrated HCl and stirred for 30 min at room temperature. The precipitated solid was filtered and dried under vacuum to give 6-vinylpyrazine-4-carboxylic acid (500 mg, 3.33 mmol, 39%) as an off-white solid, which was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 14.10 (br s, 1H), 9.42 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 18.0, 11.0Hz, 1H), 6.53 (d, J = 17.4Hz, 1H), 5.79 (d, J = 11.0Hz, 1H)

N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-vinylpyrazine-4-carboxamide

To a stirred solution of 6-vinylpyrazine-4-carboxylic acid (40 mg, 0.27 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C. under an inert atmosphere was added 6-chloro- N ² -cyclopropylpyridine -2,3-diamine Int-8 (50 mg, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinium hexafluorophosphate (170 mg, 0.32 mmol), and diisopropylethylamine ( 0.18 mL, 1.08 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with aqueous ammonium chloride (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give N- (6-chloro-2- (cyclopropylamino) pyridine-3-) as a brown solid. Yl) -6-vinylpyrazine-4-carboxamide (140 mg, crude).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 10.01 (s, 1H), 9.51 (d, J = 2.1Hz, 1H), 8.36 (d, J = 2.0Hz, 1H), 7.50 (d, J = 7.9Hz, 1H), 6.86 (d, J = 2.5Hz, 1H), 6.70-6.65 (m, 1H), 6.47 (d, J = 17.7Hz, 1H), 5.83 (d, J = 11.4Hz, 2H) , 2.73-2.69 (m, 1H), 0.73-0.68 (m, 2H), 0.49-0.45 (m, 2H)

LC-MS: m / z 316.1 [M + H] ⁺ at 2.36 RT (70.07% purity)

5-chloro-3-cyclopropyl-2- (6-vinylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine

Under an inert atmosphere, N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-vinylpyrazine-4-carboxamide (140 mg, 0.44 mmol ) To a stirred solution in third butanol (10 mL) was added tripotassium phosphate (222 mg, 1.1 mmol). The reaction mixture was heated to 90 ° C and stirred for 2 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 60-70% EtOAc / hexane) to give 5-chloro-3-cyclopropyl-2- (6-vinyl taba) as a brown slurry. oxazin-4-yl) -3 H - imidazo [4,5- b] pyridine (125mg, crude material).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 10.01 (s, 1H), 9.51 (d, J = 1.7Hz, 1H), 8.36 (d, J = 1.7Hz, 1H), 7.50 (d, J = 8.1Hz, 1H), 6.67 (d, J = 8.1Hz, 1H), 6.48 (d, J = 17.4Hz, 1H), 5.83 (d, J = 11.0Hz, 1H), 2.72-2.68 (m, 1H) , 0.72-0.68 (m, 2H), 0.49-0.44 (m, 2H)

LC-MS: m / z 297.9 [M + H] ⁺ at 2.35 RT (77.28% purity)

5- (5-chloro-3-cyclopropyl- 3H -imidazo [4,5- b ] pyridin-2-yl) pyrazine-3-carboxaldehyde

Under an inert atmosphere, 5-chloro-3-cyclopropyl-2- (6-vinylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (125 mg (0.42 mmol) in acetone: ^t BuOH: water (1: 1: 1, 7.5 mL) was added sodium periodate (179 mg, 0.84 mmol) and osmium tetroxide (1% in toluene, 2.5 mL) . The reaction mixture was gradually warmed to RT and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through diatomaceous earth pad and the bed was washed with CH ₂ Cl ₂ (30mL) with. The organic layer was washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 5- (5-chloro-3-cyclopropyl-3 H -imidazo [4,5 as a brown solid -b ] pyridin-2-yl) pyridazin-3-carboxaldehyde 8 (130 mg), which was used in the next step without further purification.

5-chloro-3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (Ex. 73)

Under an inert atmosphere, 5- (5-chloro-3-cyclopropyl- 3H -imidazo [4,5- b ] pyridin-2-yl) pyridazin-3-carboxaldehyde (130 mg, the crude material) was stirred in the in CH ₂ Cl ₂ (10mL) was added DAST (0.11mL, 0.86mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice water (20 mL) and basified with aqueous sodium carbonate (10 mL) and extracted with CH ₂ Cl ₂ (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give 5-chloro-3-cyclopropyl-2- (6- (difluoro) as an off-white solid. methyl) pyridazin-4-yl) -3 H - imidazo [4,5- b] pyridine Ex.73 (7.2mg, 0.022mmol, 5% ).

¹ H NMR (400MHz, CD ₃ OD): δ 10.00 (d, J = 2.0Hz, 1H), 8.64 (d, J = 2.0Hz, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.43 ( d, J = 8.4Hz, 1H), 7.33-7.05 (m, 1H), 3.90-3.82 (m, 1H), 1.28-1.25 (m, 2H), 0.99-0.93 (m, 2H)

LC-MS: m / z 321.9 [M + H] ⁺ at 2.56 RT (94.15% purity)

HPLC: 92.45%

3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (Ex. 76)

5-Chloro-3-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine at room temperature Ex.73 (50 mg, 0.15 mmol) in a stirred solution of DMF (2 mL) was added zinc cyanide (36 mg, 0.31 mmol) and the mixture was rinsed under argon for 5 min. Pd (PPh ₃ ) ₄ (17.94 mg, 0.01 mmol) was added and the mixture was flushed under argon for 5 min. The reaction mixture was heated to 150 ° C. under microwave for 1.5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give 3-cyclopropyl-2- (6- (difluoromethyl)) as an off-white solid. oxazin-4-yl) -3 H - imidazo [4,5- b] pyridine-5-carbonitrile Ex.76 (27mg, 0.086mmol, 56% ).

¹ H NMR (400MHz, CD ₃ OD) : δ 10.05 (d, J = 2.0Hz, 1H), 8.70 (d, J = 2.1Hz, 1H), 8.33 (d, J = 8.3Hz, 1H), 7.88 ( d, J = 8.2Hz, 1H), 7.36-7.08 (m, 1H), 3.94-3.89 (m, 1H), 1.35-1.29 (m, 2H), 1.03-0.97 (m, 2H)

LC-MS: m / z 312.9 [M + H] ⁺ at 2.11 RT (99.81% purity)

HPLC: 99.53%

[Example 74]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5-methylpyrazine-4-carboxamide

To a stirred solution of N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (250 mg, 1.35 mmol) in EtOAc (8 mL) at 0 ° C under an inert atmosphere. 5-chloropyrazine-4-carboxylic acid (206 mg, 1.49 mmol), triethylamine (0.37 mL, 2.71 mmol), and propylphosphonic anhydride (50% in EtOAc, 2.1 mL, 3.39 mmol). The reaction mixture was stirred at room temperature for 4 h. After consuming the starting material (by TLC), the reaction mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under pressure. The crude material was purified by silica gel column chromatography (eluent: 50-70% EtOAc / hexane) to obtain N- (2- (cyclopropylamino) -4,5- as a pale yellow solid. Difluorophenyl) -5-methylpyrazine-4-carboxamide (210 mg, 0.69 mmol, 51%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.78 (s, 1H), 9.36 (s, 1H), 9.26 (s, 1H), 7.47 (dd, J = 12.1, 8.7Hz, 1H), 6.94 ( dd, J = 13.4, 8.1Hz, 1H), 5.85 (s, 1H), 2.43 (s, 3H), 2.12-2.03 (m, 1H), 0.78-0.71 (m, 2H), 0.46-0.39 (m, 2H)

LC-MS: m / z 305.1 [M + H] ⁺ at 2.47 RT (72.24% purity)

1-cyclopropyl-5,6-difluoro-2- (5-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.74)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5-methylpyrazine-4-carboxamide (150 mg, 0.49 mmol) in ethanol (3 mL The stirred solution in) was added 6N HCl (3 mL). The reaction mixture was stirred at 50 ° C for 1 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was basified with a saturated sodium bicarbonate solution (30 mL) and extracted with CH ₂ Cl ₂ (40 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was washed with diethyl ether (5 mL) to give 1-cyclopropyl-5,6-difluoro-2- (5-methyldazin-4-yl) -1 H -benzo [ d ] Imidazole Ex. 74 (65 mg, 0.21 mmol, 46%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.47 (s, 1H), 9.36 (s, 1H), 7.87-7.81 (m, 2H), 3.75-3.69 (m, 1H), 2.44 (s, 3H ), 0.99-0.94 (m, 2H), 0.63-0.58 (m, 2H)

LC-MS: m / z 287.0 [M + H] ⁺ at 2.26 RT (98.32% purity)

HPLC: 99.05%

[Example 75]

6-chloro- N- (4-cyano-2- (cyclopropylamino) phenyl) pyrazine-4-carboxamide

To a stirred solution of 6-chloropyridazine-4-carboxylic acid (458 mg, 2.89 mmol) in EtOAc (30 mL) at 0 ° C under an inert atmosphere was added 4-amino-3- (cyclopropylamino) benzene Nitrile Int-6 (500 mg, 2.89 mmol), triethylamine (0.8 mL, 5.78 mmol) and propylphosphonic anhydride (50% in EtOAc, 4.6 mL, 7.22 mmol). The reaction mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC), the reaction mixture was poured into a saturated sodium bicarbonate solution (70 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (120 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 6-chloro- N- (4-cyano-2- (cyclopropylamine) as a pale yellow solid. (Yl) phenyl) pyridazine-4-carboxamide (650 mg, 2.07 mmol, 72%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 10.17 (s, 1H), 9.63 (d, J = 1.8Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.31 (d, J = 1.8Hz, 1H), 7.10 (dd, J = 8.0, 1.9Hz, 1H), 6.31 (s, 1H), 2.45-2.38 (m, 1H), 0.82- 0.77 (m, 2H), 0.48-0.43 (m, 2H)

LC-MS: m / z 312.1 [MH] - in 2.57 RT (80.47% purity)

2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile

Under an inert atmosphere, 6-chloro- N- (4-cyano-2- (cyclopropylamino) phenyl) pyridazine-4-carboxamide (600 mg, 1.91 mmol) in ethanol was added at room temperature. (6 mL) of the stirred solution was added 6 N HCl (9 mL). The reaction mixture was stirred for 10 min at 55-60 ° C. After consuming the starting material (by TLC), the reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 1% MeOH / CH ₂ Cl ₂ ) to obtain 2- (6-chloropyrazin-4-yl) -1-cyclopropane as an off-white solid. 1H -benzo [ d ] imidazole-6-carbonitrile (450 mg, 1.52 mmol, 80%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.82 (d, J = 1.9Hz, 1H), 8.20 (d, J = 1.8Hz, 1H), 8.02 (dd, J = 1.4, 0.7Hz, 1H), 7.91 (dd, J = 8.5,0.7Hz, 1H ), 7.63 (dd, J = 8.4,1.5Hz, 1H), 3.75-3.69 (m, 1H), 1.45-1.39 (m, 2H), 0.94-0.89 (m , 2H)

LC-MS: m / z 295.9 [M + H] ⁺ at 2.40 RT (95.15% purity)

1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.75)

Under an inert atmosphere at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (100 mg, 0.33 mmol) To a stirred solution in toluene: water (3: 1, 3.2 mL) was added cyclopropylboronic acid (35 mg, 0.40 mmol) and cesium carbonate (275.5 mg, 0.84 mmol) and the mixture was rinsed under argon for 5 min. Pd (dppf) Cl _2. CH ₂ Cl ₂ (27.6 mg, 0.03 mmol) was added to the reaction mixture at room temperature and the mixture was degassed under argon for 5 min. The reaction mixture was stirred at 100 ° C for 5 h. After consuming the starting material (by TLC), the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6-cyclopropylpyridazine-4 as an off-white solid. - yl) -1 H - benzo [d] imidazole-6-carbonitrile Ex.75 (40mg, 0.13mmol, 39% ).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.61 (d, J = 2.1Hz, 1H), 8.00 (s, 1H), 7.89 (dd, J = 8.4, 0.5Hz, 1H), 7.86 (d, J = 2.0Hz, 1H), 7.61 (dd, J = 8.3, 1.4Hz, 1H), 3.72-3.66 (m, 1H), 2.32-2.26 (m, 1H), 1.37-1.32 (m, 4H), 1.27-1.21 (m, 2H), 0.89-0.85 (m, 2H)

LC-MS: m / z 302 [M + H] ⁺ at 2.06 RT (96.07% purity)

HPLC: 95.17%

[Example 77]

N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) methanesulfonamide (Ex .77)

(5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methylamine at 0 ° C under an inert atmosphere A stirred solution of Int-28 (200 mg, crude material) in CH ₂ Cl ₂ (13 mL) was added triethylamine (0.18 mL, 1.32 mmol) and methanesulfonyl chloride (0.08 mL, 0.74 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with CH ₂ Cl ₂ (40 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) Azin -3-yl) methyl) methanesulfonamide Ex.77 (11 mg, 0.029 mmol, 4% overall yield).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.72 (d, J = 2.0Hz, 1H), 8.50 (d, J = 2.0Hz, 1H), 7.73 (dd, J = 10.1,7.1Hz, 1H), 7.64 (dd, J = 10.4, 7.3Hz, 1H), 4.73 (s, 2H), 3.88-3.81 (m, 1H), 3.09 (s, 3H), 1.37-1.32 (m, 2H), 0.86-0.81 ( m, 2H)

LC-MS: m / z 380.1 [M + H] ⁺ at 1.99 RT (96.14% purity)

HPLC: 98.32%

[Example 78]

1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -N -methylmethylamine

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( A stirred solution of 200 mg, 0.66 mmol) in THF (10 mL) was added dropwise a methylamine solution (2M in THF, 0.66 mL, 1.33 mmol). The reaction was warmed to room temperature and stirred for 15 min, and then cooled to 0 ° C. Sodium triacetoxyborohydride was added and the reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (40 mL) and washed with a saturated sodium bicarbonate solution (30 mL) and water (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole as an off-white solid. 2-yl) pyridazin-3-yl) -N-methylmethylamine (180 mg). The crude material was used in the next step without further purification.

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.69 (d, J = 2.1Hz, 1H), 8.30 (d, J = 2.1Hz, 1H), 7.90-7.80 (m, 2H), 4.07 (s, 2H), 3.95-3.87 (m, 1H), 2.90 (br s, 1H), 2.34 (s, 3H), 1.22-1.16 (m, 2H), 0.78-0.73 (m, 2H)

LC-MS: m / z 315.9 [M + H] ⁺ at 1.65 RT (90.51% purity)

N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) -N -methylmethyl Sulfonamide (Ex. 78)

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 ° C under an inert atmosphere. -A stirred solution of N -methylmethylamine (200 mg, crude material) in CH ₂ Cl ₂ (13 mL) was added triethylamine (0.17 mL, 1.26 mmol) and methanesulfonyl chloride (0.08 mL, 0.95 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by LCMS), the reaction mixture was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 80% EtOAc / hexane) to give N -((5- (1-cyclopropyl-5,6-difluoro- 1H -Benzo [ d ] imidazol-2-yl) pyrazin -3-yl) methyl) -N-methylmethanesulfonamide Ex.78 (35 mg, 0.089 mmol, 14%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.80 (d, J = 2.1Hz, 1H), 8.27 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 10.9, 7.5Hz, 1H) , 7.84 (dd, J = 10.4,7.3, Hz, 1H), 4.73 (s, 2H), 3.93-3.87 (m, 1H), 3.08 (s, 3H), 2.87 (s, 3H), 1.23-1.18 ( m, 2H), 0.82-0.77 (m, 2H)

LC-MS: m / z 394.1 [M + H] ⁺ at 2.43 RT (99.69% purity)

HPLC : 99.74%

[Example 79]

N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane-2-sulfonyl Amine (Ex.79)

(5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methylamine at 0 ° C under an inert atmosphere A stirred solution of Int-28 (150 mg, 0.49) in CH ₂ Cl ₂ (7 mL) was added triethylamine (0.13 mL, 0.99 mmol) and propane-2-sulfosulfanyl chloride (106 mg, 0.74 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was diluted with CH ₂ Cl ₂ (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ), which was further purified by preliminary HPLC to obtain N -((5- (1-ring Propyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin -3-yl) methyl) propane-2-sulfonamide Ex.79 (40mg, 0.09mmol , 20%).

¹ H NMR (500 MHz, DMSO- d ₆ ) : δ 9.78 (d, J = 1.7 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 7.96-7.81 (m, 3H), 4.62 (d, J = 5.8Hz, 2H), 3.91-3.85 (m, 1H), 3.30-3.27 (m, 1H), 1.28-1.21 (m, 8H), 0.79-0.74 (m, 2H)

LC-MS: m / z 408.0 [M + H] ⁺ at 2.49 RT (98.74% purity)

HPLC : 95.26%

[Example 80]

1-cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100 mg, 0.32) of a stirred solution in DMF (1 mL) was added sodium methanethiolate (15% in water, 23 mg, 0.32 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC & LC-MS), the reaction mixture was diluted with brine solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (60 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was washed with n-pentane (5 mL) and dried under vacuum to give 1-cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazine-4- as a light brown solid yl) -1 H - benzo [d] imidazole (80mg, 0.25mmol, 77%) .

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.79-9.49 (m, 1H), 8.15-7.88 (m, 1H), 7.59 (dd, J = 10.1, 7.3Hz, 1H), 7.42 (dd, J = 9.7 , 6.9Hz, 1H), 3.65-3.58 (m, 1H), 2.80 (s, 3H), 1.33-1.28 (m, 2H), 0.87-0.82 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.32 RT (97.39% purity)

1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfonyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 80)

To 1-cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] at 0 ° C under an inert atmosphere A stirred solution of imidazole (60 mg, 0.18 mmol) in CH ₂ Cl ₂ (6 mL) was added m-chloroperoxybenzoic acid (81 mg, 0.47 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h. After consuming the starting material (by TLC & LC-MS), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (60 mL), dried over brine-free Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- ( sulfo acyl methyl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.80 (30mg, 0.085mmol, 45% ).

¹ H NMR (400 MHz, CDCl ₃ ) : δ 10.09 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 9.9, 7.3 Hz, 1H), 7.46 (dd, J = 9.5, 6.9Hz, 1H), 3.74-3.68 (m, 1H), 3.52 (s, 3H), 1.44-1.37 (m, 2H), 0.94-0.87 (m, 2H)

LC-MS: m / z 351.0 [M + H] ⁺ at 2.64 RT (95.45% purity)

HPLC : 96.64%

[Example 81 & Example 83]

1-cyclopropyl-2- (6- (ethylthio) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 300 mg, 0.98) in a stirred solution of DMF (7 mL) was added sodium ethanethiolate (15% in water, 90 mg, 1.07 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (40 mL), dried over brine-free Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was washed with n-pentane (5 mL) and dried under vacuum to give 1-cyclopropyl-2- (6- (ethylthio) pyridazin-4-yl) -5,6- as a pale off-white solid Difluoro-1 H -benzo [ d ] imidazole (240 mg, 0.72 mmol, 74%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.49 (d, J = 2.0Hz, 1H), 7.86 (d, J = 2.0Hz, 1H), 7.58 (dd, J = 10.2,7.3Hz, 1H), 7.42 (dd, J = 9.7,6.9Hz, 1H), 3.65-3.57 (m, 1H), 3.44 (q, J = 7.4Hz, 2H), 1.49 (t, J = 7.3Hz, 3H), 1.33-1.29 ( m, 2H), 0.88-0.83 (m, 2H)

1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.81) & 1- Cyclopropyl-2- (6- (ethylsulfinamidino) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 83)

To 1-cyclopropyl-2- (6- (ethylthio) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] at 0 ° C under an inert atmosphere. A stirred solution of imidazole (260 mg, 0.78) in CH ₂ Cl ₂ (8 mL) was added m-chloroperoxybenzoic acid (296 mg, 1.56 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (60mL), was no washing Na ₂ SO ₄ dried and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50-70% EtOAc / hexane) to obtain 1-cyclopropyl-2- (6- (ethylsulfonyl)) as an off-white solid. Pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex.81 (22 mg, 0.060 mmol) & 1-cyclopropyl-2- (6- ( Ethylsulfinyl) pyridazin-4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 83 (60 mg, 0.17 mmol).

[Analytical data of Ex.81]

¹ H NMR (400MHz, CD ₃ OD) : δ 10.08 (d, J = 2.0Hz, 1H), 8.89 (d, J = 2.0Hz, 1H), 7.74 (dd, J = 10.1, 7.1Hz, 1H), 7.67 (dd, J = 10.3,7.3Hz, 1H), 3.96-3.89 (m, 1H), 3.69 (q, J = 7.4Hz, 2H), 1.39 (t, J = 7.4Hz, 3H), 1.33-1.27 (m, 2H), 0.93-0.86 (m, 2H)

LC-MS: m / z 365.0 [M + H] ⁺ at 2.72 RT (99.37% purity)

HPLC : 95.47%

[Analytical data of Ex.83]

¹ H NMR (400MHz, CD ₃ OD) : δ 9.93 (d, J = 2.1Hz, 1H), 8.76 (d, J = 2.1Hz, 1H), 7.75 (dd, J = 10.1, 7.1Hz, 1H), 7.67 (dd, J = 10.4,7.3Hz, 1H), 3.94-3.89 (m, 1H), 3.49-3.42 (m, 1H), 3.27-3.19 (m, 1H), 1.35-1.31 (m, 2H), 1.29 (t, J = 7.3Hz, 3H), 0.92-0.88 (m, 2H).

LC-MS: m / z 348.9 [M + H] ⁺ at 2.09 RT (95.88% purity)

HPLC : 95.47%

[Example 82]

1-cyclopropyl-5,6-difluoro-2- (6- (methylthiopyridazin-4-yl) -1 H -benzo [ d ] imidazole

Under an inert atmosphere at 0 ° C to 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( 100 mg, 0.32) of a stirred solution of DMF (1 mL) in sodium methanethiolate (15% in water, 23 mg, 0.32 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consuming the starting material (by TLC & LC-MS), the reaction mixture was diluted with brine solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (60 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was washed with n-pentane (5 mL) and dried under vacuum to give 1-cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazine-4- as a light brown solid yl) -1 H - benzo [d] imidazole (80mg, 0.25mmol, 77%) .

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.79-9.49 (m, 1H), 8.15-7.88 (m, 1H), 7.59 (dd, J = 10.1, 7.3Hz, 1H), 7.42 (dd, J = 9.7 , 6.9Hz, 1H), 3.65-3.58 (m, 1H), 2.80 (s, 3H), 1.33-1.28 (m, 2H), 0.87-0.82 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.32 RT (97.39% purity)

1-Cyclopropyl-5,6-difluoro-2- (6- (methylsulfinamidinyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 82)

To 1-cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] at 0 ° C under an inert atmosphere A stirred solution of imidazole (100 mg, 0.31 mmol) in CH ₂ Cl ₂ (6 mL) was added m-chloroperoxybenzoic acid (59 mg, 0.34 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (60mL), was no washing Na ₂ SO ₄ dried and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 60-70% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6- (acyl methylsulfinyl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.82 (15mg, 0.04mmol, 14% ).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.95 (d, J = 2.1Hz, 1H), 8.78 (d, J = 2.1Hz, 1H), 7.63 (dd, J = 10.0, 7.3Hz, 1H), 7.45 (dd, J = 9.5, 6.9Hz, 1H), 3.76-3.68 (m, 1H), 3.08 (s, 3H), 1.39-1.34 (m, 2H), 0.92-0.87 (m, 2H)

LC-MS: m / z 335 [M + H] ⁺ at 2.23 RT (95.79% purity)

HPLC : 96.90%

[Example 84]

6-chloropyrazine-4-carboxylic acid methyl ester

To a stirred solution of 6-chloropyrazine-4-carboxylic acid (1.5 g, 9.49 mmol) in CH ₂ Cl ₂ (30 mL) at 0 ° C. under argon atmosphere was added diazomethane in diethyl ether (by N -nitrosomethylurea (3 g) was added to a mixture of 50% KOH solution (25 mL) and diethyl ether (50 mL) at 0 ° C to prepare freshly). The reaction was warmed to RT and stirred for 30 min. After consumption of the starting material (by TLC), the reaction mixture was filtered through diatomaceous earth and the pad was washed with CH ₂ Cl ₂ (30mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to obtain methyl 6-chloropyrazine-4-carboxylate (1.4 g, 8.13 mmol, 86%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.58 (d, J = 1.6Hz, 1H), 8.03 (d, J = 1.8Hz, 1H), 4.04 (s, 3H)

6-cyclopropylpyridazine-4-carboxylic acid methyl ester

To a stirred solution of methyl 6-chloropyrazine-4-carboxylate (1 g, 5.81 mmol) in toluene (60 mL) was added cyclopropylboronic acid (874 mg, 10.17 mmol) and cesium carbonate (2.84 g, 8.72) mmol) and the mixture was flushed under argon for 20 min. Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (237 mg, 0.290 mmol) was added and the mixture was flushed with argon at room temperature for 5 min. The reaction mixture was heated to 100 ° C and stirred for 5 h. After consuming the starting material (by TLC), the reaction mixture was diluted with EtOAc (40 mL), filtered through a celite pad and the bed was washed with EtOAc (25 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 6-cyclopropylpyridazine-4-carboxylic acid methyl ester (600 mg, 3.37 mmol, 58 as an off-white solid). %).

¹ H NMR (400MHz, CDCl ₃ ) : δ 9.42 (d, J = 2.0Hz, 1H), 7.72 (d, J = 2.0Hz, 1H), 4.00 (s, 3H), 2.30-2.22 (m, 1H) , 1.30-1.24 (m, 2H), 1.24-1.18 (m, 2H)

LC-MS: m / z 178.9 [M + H] ⁺ at 1.70 RT (96.83% purity)

6-cyclopropylpyridazine-4-carboxylic acid

To a stirred solution of 6-cyclopropylpyridazine-4-carboxylic acid ester (400 mg, 2.24 mmol) in THF (0.6 mL) at room temperature was added lithium hydroxide (283 g, 6.74 mmol) in water (1 M, 6.7 mL) and stirred for 16 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified with concentrated HCl (pH 3-4), diluted with water (30 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 6-cyclopropylpyrazine-4-carboxylic acid (300 mg, crude material) as an off-white solid. The crude material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 14.06 (br s, 1H), 9.31 (d, J = 1.7Hz, 1H), 7.88 (d, J = 2.3Hz, 1H), 2.43-2.37 (m , 1H), 1.16-1.11 (m, 4H)

LC-MS: m / z 165.2 [M + H] ⁺ at 2.83 RT (95.00% purity)

N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-cyclopropylpyridazine-4-carboxamide

To a stirred solution of 6-cyclopropylpyridazine-4-carboxylic acid (300 mg, crude material) in THF (15 mL) under room temperature under inert atmosphere, TBTU (1.03 g, 2.74 mmol) and HOBt (259 mg, 1.92 mmol) and the reaction was stirred for 10 min. Add 6-chloro- N ² -cyclopropylpyridine-2,3-diamine Int-8 (334 mg, 1.82 mmol) and triethylamine (0.38 mL, 2.74 mmol) to the reaction mixture at room temperature and stir for 16 h . After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to obtain N- (6-chloro-2- (cyclopropylamino) pyridine-3-) as a viscous slurry. ) -6-cyclopropylpyridazine-4-carboxamide (400 mg, 1.21 mmol, 54%, over two steps).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.93 (s, 1H), 9.40 (d, J = 1.7Hz, 1H), 7.89 (d, J = 1.7Hz, 1H), 7.49 (d, J = 8.1Hz, 1H), 6.83 (d, J = 2.3Hz, 1H), 6.66 (d, J = 8.1Hz, 1H), 2.64-2.62 (m, 1H), 2.41-2.33 (m, 1H), 1.20- 1.14 (m, 2H), 1.14-1.09 (m, 2H), 0.73-0.67 (m, 2H), 0.49-0.44 (m, 2H)

LC-MS: m / z 329.9 [M + H] ⁺ at 2.54 RT (89.91% purity)

5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (Ex.84)

To an N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6-cyclopropylpyridazine-4-carboxamide at room temperature under an inert atmosphere in a sealed tube. (350mg, 1.06mmol) was stirred in ^t BuOH solution (4mL) of the potassium phosphate (676mg, 3.19mmol). The reaction mixture was heated to 110 ° C and stirred for 36 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to give 5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazine) as an off-white solid. 4-yl) -3 H - imidazo [4,5- b] pyridine Ex.84 (65mg, 0.20mmol, 19% ).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.59 (d, J = 2.0Hz, 1H), 8.13-8.08 (m, 2H), 7.42 (d, J = 8.4Hz, 1H), 3.85-3.77 (m , 1H), 2.46-2.37 (m, 1H), 1.30-1.22 (m, 6H), 0.96-0.89 (m, 2H).

LC-MS: m / z 311.9 [M + H] ⁺ at 2.44 RT (98.03% purity)

HPLC : 99.62%

[Example 85]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

To a stirred solution of N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (200 mg, 1.08 mmol) in EtOAc (12 mL) at 0 ° C under an inert atmosphere. 6- (trifluoromethyl) pyrazine-4-carboxylic acid Int-26 (208 mg, 1.08 mmol), triethylamine (0.3 mL, 2.17 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.72 g, 2.71 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give N- (2- (cyclopropylamino) -4,5-difluorobenzene as an off-white solid. ) -6- (trifluoromethyl) pyridazin-4-methylamidine (300 mg, 0.83 mmol, 77%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 10.18 (s, 1H), 9.91 (d, J = 1.7Hz, 1H), 8.67 (d, J = 1.7Hz, 1H), 7.30 (dd, J = 11.0, 8.7Hz, 1H), 6.93 (dd, J = 13.6, 7.8Hz, 1H), 6.07 (s, 1H), 2.37-2.34 (m, 1H), 0.78-0.72 (m, 2H), 0.45-0.39 (m, 2H)

LC-MS: m / z 357.0 [MH] - in 3.17 RT (95.02% purity)

1-cyclopropyl-5,6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 85)

Under an inert atmosphere, N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide ( A stirred solution of 200 mg, 0.55 mmol) in ethanol (2 mL) was added 6N HCl (2.3 mL). The reaction mixture was heated to 70 ° C and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was basified to pH 8 using saturated sodium bicarbonate solution and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane), which was further washed with n-pentane (10 mL) and dried in vacuo to give 1-cyclopropane as an off-white solid. -5,6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 85 (100 mg, 0.29 mmol, 53%).

¹ H NMR (400MHz, CD ₃ OD) : δ 10.07 (d, J = 2.0Hz, 1H), 8.69 (d, J = 2.0Hz, 1H), 7.74 (dd, J = 10.1, 7.1Hz, 1H), 7.66 (dd, J = 10.4,7.3Hz, 1H), 3.94-3.89 (m, 1H), 1.32-1.26 (m, 2H), 0.90-0.84 (m, 2H)

LC-MS: m / z 340.9 [M + H] ⁺ at 3.12 RT (97.31% purity)

HPLC : 96.06%

[Example 86]

N- (4-cyano-2- (cyclopropylamino) phenyl) -6- (trifluoromethyl) pyrazine-4-carboxamide

To a stirred solution of 4-amino-3- (cyclopropylamino) benzonitrile Int-6 (200 mg, 1.15 mmol) in EtOAc (12 mL) at room temperature under an inert atmosphere was added 6- (tri Fluoromethyl) pyridazine-4-carboxylic acid Int-26 (221 mg, 1.15 mmol) and triethylamine (0.3 mL, 2.31 mmol). The mixture was cooled to 0 ° C and propylphosphonic anhydride (T3P, 50% in EtOAc, 1.8 mL, 2.89 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give N- (4-cyano-2- (cyclopropylamino) phenyl) as an off-white solid) -6- (trifluoromethyl) pyridazine-4-carboxamide (200 mg). The crude material was used in the next step without further purification.

LC-MS: m / z 346.1 [MH] - in 2.94 RT (67.16% purity)

1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex. 86)

Under an inert atmosphere, N- (4-cyano-2- (cyclopropylamino) phenyl) -6- (trifluoromethyl) pyrazine-4-carboxamide (200 mg, Crude material) A stirred solution of EtOH (2 mL) was added 6N HCl (2 mL). The reaction mixture was heated to 70 ° C and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was cooled to room temperature, basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to obtain a residue, which was further purified by preparative HPLC to give 1-cyclopropyl- as an off-white solid. 2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 86 (40 mg, 0.066 mmol, 21%).

¹ H NMR (400MHz, CDCl ₃ ) : δ 10.10 (d, J = 2.0Hz, 1H), 8.52 (d, J = 2.0Hz, 1H), 8.04 (s, 1H), 7.94 (d, J = 8.4Hz , 1H), 7.64 (dd, J = 8.5, 1.3Hz, 1H), 3.81-3.74 (m, 1H), 1.46-1.40 (m, 2H), 0.95-0.89 (m, 2H)

LC-MS: m / z 329.9 [M + H] ⁺ at 2.80 RT (99.16% purity)

HPLC : 99.42%

[Example 87]

3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (Ex.87)

At room temperature, 2- (6-cyclopropyl-pyridazin-4-yl) -3 H 5-chloro-3-cyclopropyl sealed tube - imidazo [4,5- b] pyridine Ex. A stirred solution of 84 (50 mg, 0.16 mmol) in DMF (1 mL) was added zinc cyanide (37 mg, 0.32 mmol) and Pd (PPh ₃ ) ₄ (18.5 mg, 0.01 mmol) and the mixture was rinsed under argon for 20 min. The reaction mixture was heated to 170 ° C and stirred for 9 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 3-cyclopropyl-2- (6-cyclopropylpyridazine-4) as an off-white solid. - yl) -3 H - imidazo [4,5- b] pyridine-5-carbonitrile Ex.87 (40mg, 0.13mmol, 82% ).

¹ H NMR (400 MHz, CD ₃ OD) : δ 9.63 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 8.3 Hz, 1 H), 8.16 (d, J = 2.0 Hz, 1 H), 7.86 ( d, J = 8.3Hz, 1H), 3.90-3.83 (m, 1H), 2.48-2.41 (m, 1H), 1.32-1.25 (m, 6H), 1.00-0.94 (m, 2H)

LC-MS: m / z 303 [M + H] ⁺ at 2.27 RT (93.10% purity)

HPLC : 96.03%

[Example 88]

3-chloro- N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane- 1-sulfamethoxamine

(5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 to 5 ° C under an inert atmosphere A stirred solution of methylamine Int-28 (300 mg, 0.99 mmol) in CH ₂ Cl ₂ (10 mL) was added triethylamine (0.2 mL, 1.49 mmol) and 3-chloropropane-1-sulfosulfanyl chloride (170 mg, 0.99 mmol). ). The reaction mixture was warmed to room temperature and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with CH ₂ Cl ₂ (60mL) and washed with water (40 mL) and brine (40 mL) and washed. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 80% EtOAc / hexane) to give 3-chloro- N -((5- (1-cyclopropyl-5) as a colorless viscous slurry. , 6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane-1-sulfonamide (280 mg). This crude material was used in the next step without purification.

LC-MS: m / z 442.1 [M + H] ⁺ at 2.68 RT (90.03% purity)

2-((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) isothiazolyl 1,1 -Dioxide (Ex. 88)

Under an inert atmosphere at room temperature toward 3-chloro- N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazine To a stirred solution of 3--3-yl) methyl) propane-1-sulfonamide (200 mg, crude material) in DMF (10 mL) was added potassium carbonate (125 mg, 0.90 mmol) and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give 2-((5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl)) as a pale off-white solid. Azin -3-yl) methyl) isothiazolidine 1,1-dioxide Ex. 88 (80 mg, 0.20 mmol, 44%).

¹ H NMR (500 MHz, DMSO- d ₆ ) : δ 9.77 (d, J = 1.7 Hz, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.92-7.82 (m, 2H), 4.59 (s, 2H), 3.92-3.86 (m, 1H), 3.35-3.31 (m, 4H), 2.29 (m, 2H), 1.23-1.17 (m, 2H), 0.79-0.74 (m, 2H)

LC-MS: m / z 406.0 [M + H] ⁺ at 2.39 RT (99.55% purity)

HPLC : 97.80%

[Example 90]

N- (2- (cyclopropylamino) -4- (trifluoromethyl) phenyl) -6-methylpyrazine-4-carboxamide

At 0 ° C, N ¹ -cyclopropyl-5- (trifluoromethyl) benzene-1,2-diamine Int-19 (300 mg, crude substance) and 6-methylpyrazine- A stirred solution of 4-formic acid (266mg, 1.53mmol) in ethyl acetate (6mL) was added dropwise triethylamine (0.39mL, 2.78mmol), followed by propylphosphonic anhydride (50% in EtOAc, 2.21mL) , 3.47 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) to give N- (2- (cyclopropylamino) -4- (trifluoromethyl) as an off-white solid. ) Phenyl) -6-methylpyrazine-4-carboxamide (200 mg, 0.59 mmol, 42%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.03 (s, 1H), 9.51 (s, 1H), 8.02 (s, 1H), 7.41 (d, J = 8.1Hz, 1H), 7.23 (s, 1H), 6.98 (br d, J = 8.1Hz, 1H), 6.24 (s, 1H), 2.74 (s, 3H), 2.43-2.41 (m, 1H), 0.81-0.74 (m, 2H), 0.47- 0.45 (m, 2H)

LC-MS: m / z 337.1 [M + H] ⁺ at 2.36 RT (96.19% purity)

1-cyclopropyl-2- (6-methylpyrazin-4-yl) -6- (trifluoromethyl) -1 H -benzo [ d ] imidazole (Ex. 90)

N- (2- (cyclopropylamino) -4- (trifluoromethyl) phenyl) -6-methylpyrazine-4-carboxamide (100 mg, A stirred solution of 0.3 mmol) in ethanol (1 mL) was added dropwise 6 N HCl (1.5 mL). The mixture was warmed to 60 ° C. for 15 min in a pre-heated oil bath. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was washed with n-pentane (2 x 5 mL) and dried under vacuum to give 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -6- (trifluoromethyl) as an off-white solid ) -1 H -benzo [ d ] imidazole Ex. 90 (40 mg, 0.12 mmol, 42%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.69 (d, J = 1.9Hz, 1H), 8.21 (d, J = 2.0Hz, 1H), 8.06 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.64 (dd, J = 8.5, 1.4Hz, 1H), 4.01-3.96 (m, 1H), 2.78 (s, 3H), 1.27-1.21 (m, 2H), 0.81-0.75 (m , 2H)

LC-MS: m / z 319.0 [M + H] ⁺ at 2.61 RT (97.98% purity)

HPLC: 97.37%

[Example 91]

N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethyl) methanesulfonamide (Ex.91)

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 ° C under an inert atmosphere. A stirred solution of ethyl-1-amine Int-30 (70 mg, crude material) in CH ₂ Cl ₂ (3 mL) was added triethylamine (0.07 mL, 0.55 mmol) and methanesulfonyl chloride (0.02 mL, 0.33 mmol). The reaction mixture was warmed to room temperature and stirred for 6 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (15mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 25mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (1- (5- (1-cyclopropyl-5,6) as an off-white solid. -Difluoro - 1H -benzo [ d ] imidazol-2-yl) pyrazin- 3-yl) ethyl) methanesulfonamide Ex. 91 (36 mg, 0.09 mmol, 17%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.74 (d, J = 2.1Hz, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.93 -7.82 (m, 2H), 5.00-4.95 (m, 1H), 3.94-3.86 (m, 1H), 2.92 (s, 3H), 1.57 (d, J = 7.0Hz, 3H), 1.25-1.20 (m , 2H), 0.78-0.75 (m, 2H)

LC-MS: m / z 394.0 [M + H] ⁺ at 2.33 RT (92.93% purity)

HPLC: 97.92%

[Example 92 & Example 94]

(5- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol (Ex.94)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( 100 mg, 0.33 mmol) in a stirred solution of methanol (5 mL) was added sodium borohydride (6.3 mg, 0.16 mmol). The reaction mixture was stirred at the same temperature for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saline solution (10 mL). The volatiles were removed under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) to obtain (5- (1-cyclopropyl-5,6-difluoro-1 H- Benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol Ex.94 (30 mg, 0.099 mmol, 30%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.71 (d, J = 2.3Hz, 1H), 8.28 (d, J = 1.7Hz, 1H), 7.88-7.79 (m, 2H), 5.77 (t, J = 5.8 Hz, 1H), 4.88 (d, J = 5.8 Hz, 2H), 3.93-3.88 (m, 1H), 1.21-1.15 (m, 2H), 0.77-0.73 (m, 2H)

LC-MS: m / z 302.9 [M + H] ⁺ at 2.39 RT (95.96% purity)

HPLC : 96.82%

1-cyclopropyl-5,6-difluoro-2- (6- (fluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 92)

To (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol Ex at 0 ° C under an inert atmosphere A stirred solution of .94 (130 mg, 0.43 mmol) in CH ₂ Cl ₂ (3 mL) was added DAST (0.16 mL, 210 mg, 1.29 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium carbonate solution (20 mL) and extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane), which was further purified by preparative HPLC to give 1-cyclopropyl-5,6-difluoro as an off-white solid. -2- (6- (fluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 92 (10 mg, 0.03 mmol, 8%).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.80 (d, J = 1.9Hz, 1H), 8.44 (d, J = 2.1Hz, 1H), 7.73 (dd, J = 10.1, 7.1Hz, 1H), 7.64 (dd, J = 10.4,7.3Hz, 1H), 5.89 (s, 1H), 5.78 (s, 1H), 3.90-3.85 (m, 1H), 1.31-1.24 (m, 2H), 0.87-0.81 ( m, 2H)

LC-MS: m / z 304.9 [M + H] ⁺ at 2.53 RT (99.54% purity)

HPLC: 99.73%.

[Example 93]

[Program]

Ethyl 3-hydrazino-3-oxopropanoate

Under a inert atmosphere, to a stirred solution of diethyl malonate (50 g, 312.5 mmol) in ethanol (32 mL) was added hydrazine hydrate (5 mL, 103.12 mmol) at room temperature and stirred for 16 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 1% MeOH / CH ₂ Cl ₂ ) to obtain ethyl 3-hydrazino-3- pendant propionate (6 g, 41.09) as an off-white solid. mmol, 13%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 9.16 (brs, 1 H), 4.28 (brs, 2 H), 4.07 (q, J = 7.1 Hz, 2 H), 3.40 (s, 2H), 1.20 -1.16 (m, 3H)

LC-MS: m / z 147.2 [M + H] ⁺ at 3.53 RT (89.08% purity)

( E ) -3-Ethoxy-3- (2- (3-oxobut-2-yl) hydrazino) propionic acid ethyl ester

To a stirred solution of ethyl 3-hydrazino-3-oxopropanoate (6 g, 41.09 mmol) in ethanol (120 mL) at room temperature under inert atmosphere was added diethylpyrene (3.5 g, 41.09 mmol). And stirred for 16h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give ( E ) -3-sideoxy-3- (2- (3-side oxygen) as an off-white solid. Butyl-2-ylidene) hydrazino) ethyl propionate (6 g, 28.03 mmol, 69%).

¹ H NMR (400 MHz, DMSO- d ₆ ) : δ 11.18 (brs, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 2.27 (s, 3H), 1.90 (s, 3H), 1.16 (t, J = 7.1Hz, 3H)

LC-MS: m / z 215 [M + H] ⁺ at 1.69 RT (93.82% purity)

Ethyl 5,6-dimethyl-3-oxo-2,3-dihydropyrazine-4-carboxylic acid

Under an inert atmosphere, ethyl ( E ) -3-oxo-3- (2- (3-oxobut-2-yl) hydrazino) propanoate (3g, 14.01mmol) ) To a stirred solution in 1,4-dioxane (30 mL) was added 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) (2.08 mL, 14.01 mmol). The reaction mixture was heated to 100 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 5,6-dimethyl-3- pendantoxy-2,3-dihydropyridazine-4 as a colorless viscous slurry. -Ethyl formate (1.5 g, crude). This crude material was used in the next step without further purification.

¹ H NMR (500 MHz, DMSO- d ₆ ) : δ 12.97 (brs, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 2.09 (s, 3H), 1.27 (t, J = 7.0Hz, 3H)

LC-MS: m / z 196.9 [M + H] ⁺ at 1.50 RT (46.75% purity)

3-chloro-5,6-dimethylpyrazine-4-carboxylic acid ethyl ester

Under an inert atmosphere at 0 ° C, ethyl 5,6-dimethyl-3- pendantoxy-2,3-dihydropyridazine-4-carboxylic acid (1.5 g, crude material) To a stirred solution in 1,4-dioxane (25 mL) was added phosphonium trichloride (7.3 mL, 76.53 mmol). The reaction mixture was heated to 100 ° C and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give ethyl 3-chloro-5,6-dimethylpyrazine-4-carboxylic acid as a colorless viscous slurry. Esters (250 mg, 1.16 mmol, 8% over two steps).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 4.46 (q, J = 7.2Hz, 2H), 2.63 (s, 3H), 2.28 (s, 3H), 1.34 (t, J = 7.1Hz, 3H)

LC-MS: m / z 214.9 [M + H] ⁺ at 2.19 RT (97.49% purity)

Ethyl 5,6-dimethylpyrazine-4-carboxylate

To a stirred solution of ethyl 3-chloro-5,6-dimethylpyrazine-4-carboxylate (250 mg, 1.16 mmol) in ethanol (12 mL) was added triethylamine (catalyst at room temperature under an inert atmosphere). ) And 10% Pd / C (50% wet, 120 mg). The reaction was vented and a hydrogen atmosphere (ball pressure) was established and the reaction was stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure. The obtained crude substance was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to obtain ethyl 5,6-dimethylpyrazine-4-carboxylate (100 mg as a colorless slurry) , 0.55 mmol, 48%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.14 (s, 1H), 4.36 (q, J = 7.1Hz, 2H), 2.66 (s, 3H), 2.44 (s, 3H), 1.33 (t, J = 7.2Hz, 3H)

LC-MS: m / z 180.9 [M + H] ⁺ at 1.76 RT (98.17% purity)

5,6-dimethylpyrazine-4-carboxylic acid

To a stirred solution of ethyl 5,6-dimethylpyrazine-4-carboxylate (100 mg, 0.55 mmol) in a mixture of THF: water (2: 1,2 mL) at 0 ° C was added lithium hydroxide monohydrate (47 mg, 1.11 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the volatiles were concentrated under reduced pressure. Subsequently, the residue was diluted with water (5 mL) and acidified using a concentrated HCl solution (about pH 3-4). The aqueous layer was lyophilized to give 5,6-dimethylpyrazine-4-carboxylic acid (110 mg, salt) as a white solid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ ) : δ 9.17 (s, 1H), 2.69 (s, 3H), 2.48 (s, 3H)

LC-MS: m / z 153.2 [M + H] ⁺ at 1.79 RT (99.78% purity)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5,6-dimethylpyrazine-4-carboxamide

To a stirred solution of 5,6-dimethylpyrazine-4-carboxylic acid (67 mg, crude material) in EtOAc (5 mL) was added N ¹ -cyclopropyl-4,5- at 0 ° C under an inert atmosphere. Difluorobenzene-1,2-diamine Int-5 (80 mg, 0.43 mmol), triethylamine (0.24 mL, 1.75 mmol), and propylphosphonic anhydride (50% in EtOAc, 0.7 mL, 1.09 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 60% EtOAc / hexane) to obtain N- (2- (cyclopropylamino) -4,5-difluorobenzene as a brown solid. Yl) -5,6-dimethylpyrazine-4-carboxamide (40 mg, 0.12 mmol, 29%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 9.76 (s, 1H), 9.18 (s, 1H), 7.51 (dd, J = 11.9, 8.4Hz, 1H), 6.67 (dd, J = 10.7, 7.2 Hz, 1H), 5.78 (s, 1H), 2.66 (s, 3H), 2.60-2.55 (m, 1H), 2.34 (s, 3H), 1.43-1.34 (m, 2H), 0.44-0.40 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.90 RT (49.24% purity).

1-cyclopropyl-2- (5,6-dimethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.93)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5,6-dimethylpyridazine-4-methyl in a sealed tube at room temperature under an inert atmosphere To a stirred solution of amidine (40 mg, 0.125 mmol) in tBuOH (0.5 mL) was added tripotassium phosphate (66 mg, 0.31 mmol). The reaction mixture was heated to 120 ° C and stirred for 6 h. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (5,6-dimethylpyrazine as an off-white solid. -4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 93 (18 mg, 0.06 mmol, 48%).

¹ H NMR (400MHz, CD ₃ OD) : δ 9.18 (s, 1H), 7.71 (dd, J = 10.1, 7.1Hz, 1H), 7.61 (dd, J = 10.5, 7.2Hz, 1H), 3.63-3.55 (m, 1H), 2.80 (s, 3H), 2.39 (s, 3H), 1.06-1.00 (m, 2H), 0.72-0.66 (m, 2H)

LC-MS: m / z 300.9 [M + H] ⁺ at 2.34 RT (99.49% purity)

HPLC: 99.17%

[Example 95 & Example 89]

N- (6-chloro-2- (cyclopropylamino) pyridin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

To a stirred solution of 6-chloro- N ² -cyclopropylpyridine-2,3-diamine Int-8 (300 mg, 1.63 mmol) in EtOAc (10 mL) was added 6 at 0 to 5 ° C under an inert atmosphere. -(Trifluoromethyl) pyrazine-4-carboxylic acid Int-26 (314mg, 1.63mmol), triethylamine (0.43mL, 3.27mmol) and propylphosphonic anhydride (50% in EtOAc, 2.6mL, 4.09mmol ). The reaction mixture was warmed to room temperature and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to obtain N- (6-chloro-2- (cyclopropylamino) pyridine-3-) as a brown solid. ) -6- (trifluoromethyl) pyridazine-4-carboxamide (250 mg, 0.70 mmol, 43%).

¹ H NMR (500MHz, DMSO- d ₆ ) : δ 10.24 (s, 1H), 9.92 (s, 1H), 8.67 (d, J = 1.7Hz, 1H), 7.49 (d, J = 8.1Hz, 1H) , 6.87 (d, J = 1.7 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 2.72-2.67 (m, 1H), 0.74-0.69 (m, 2H), 0.49-0.44 (m, 2H )

LC-MS: m / z 357.9 [M + H] ⁺ at 2.87 RT (96.94% purity)

5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (Ex. 95)

N- (6-Chloro-2- (cyclopropylamino) pyridin-3-yl) -6- (trifluoromethyl) pyridazine-4- To a stirred solution of formamidine (200 mg, 0.56 mmol) in ^t BuOH (6 mL) was added tripotassium phosphate (400 mg). The reaction mixture was stirred at 130 ° C for 24 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 25% EtOAc / hexane) to give 5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) as an off-white solid. ) pyridazin-4-yl) -3 H - imidazo [4,5- b] pyridine Ex.95 (150mg, 0.44mmol, 79% ).

¹ H NMR (400 MHz, CD ₃ OD) : δ 10.13 (d, J = 2.0 Hz, 1 H), 8.76 (d, J = 2.0 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.44 ( d, J = 8.5Hz, 1H), 3.91-3.84 (m, 1H), 1.32-1.26 (m, 2H), 1.00-0.95 (m, 2H)

LC-MS: m / z 339.9 [M + H] ⁺ at 2.86 RT (97.81% purity)

HPLC: 98.06%

3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (Ex. 89)

5-Chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] in a sealed tube at room temperature A stirred solution of pyridine Ex. 95 (90 mg, 0.26 mmol) in DMF (1.5 mL) was added zinc cyanide (62 mg, 0.53 mmol) and Pd (PPh ₃ ) ₄ (30 mg, 0.02 mmol) and the mixture was rinsed under argon 10min. The reaction mixture was heated to 170 ° C for 8 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with diethyl ether (2 x 10 mL) and dried under vacuum. The obtained solid was further purified by preparative HPLC System to afford an off-white solid by 3-cyclopropyl-2- (6- (trifluoromethyl) pyridazine-4-yl) -3 H - imidazo [4, 5- b ] pyridine-5-carbonitrile Ex. 89 (13 mg, 0.039 mmol, 15%).

¹ H NMR (400MHz, CD ₃ OD): δ 10.16 (d, J = 2.0Hz, 1H), 8.81 (d, J = 2.0Hz, 1H), 8.34 (d, J = 8.3Hz, 1H), 7.87 ( d, J = 8.2Hz, 1H), 3.96-3.88 (m, 1H), 1.35-1.28 (m, 2H), 1.03-0.97 (m, 2H)

LC-MS: m / z 331.2 [M + H] ⁺ at 3.41 RT (99.80% purity)

HPLC: 99.55%

[Example 96]

N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazol-2-yl) pyrazin-3-yl) ethyl) ethanesulfonamide (Ex.96)

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) at 0 ° C under an inert atmosphere. A stirred solution of ethyl-1-amine Int-30 (70 mg, 0.22 mmol) in CH ₂ Cl ₂ (5 mL) was added triethylamine (0.07 mL, 0.55 mmol) and ethanesulfonyl chloride (43 mg, 0.33 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 30mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by preparative HPLC to give N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) as an off-white solid. Pyrazin- 3-yl) ethyl) ethanesulfonamide ( Ex. 96 ) (40 mg, 0.09 mmol, 44%).

¹ H NMR (400MHz, DMSO-d ₆ ) : δ 9.74 (d, J = 2.0Hz, 1H), 8.39 (d, J = 2.1Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.92 -7.81 (m, 2H), 4.92 (p, J = 7.3Hz, 1H), 3.93-3.86 (m, 1H), 3.11-2.90 (m, 2H), 1.57 (d, J = 7.0Hz, 3H), 1.27-1.20 (m, 2H), 1.16 (t, J = 7.3Hz, 3H), 0.80-0.72 (m, 2H)

LC-MS: m / z 408.0 [M + H] ⁺ at 2.42 RT (98.97% purity)

HPLC: 99.61%

[Example 97]

2- (6-butylpyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 97)

Under an inert atmosphere, in a sealed tube, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] A stirred solution of imidazole Ex.22 (300mg, 0.98mmol ) in toluene (5mL) was added with X-phos (47mg, 0.1mmol), tripotassium phosphate (623mg, 2.94mmol) and butylboronic acid (148 mg, 1.47mmol) . The reaction mixture was flushed under argon for 15 min. Pd ₂ (dba) ₃ (90 mg, 0.1 mmol) was added at room temperature and the reaction mixture was heated to 100 ° C. and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain a residue, which was further purified by normal phase preparative HPLC to obtain an off-white solid. 2- (6-butylpyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 97 (20 mg, 0.06 mmol, 6%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.63 (d, J = 2.1Hz, 1H), 8.20 (d, J = 2.1Hz, 1H), 7.71 (dd, J = 10.1, 7.1Hz, 1H), 7.62 (dd, J = 10.4,7.3Hz, 1H), 3.90-3.84 (m, 1H), 3.15-3.09 (m, 2H), 1.90-1.81 (m, 2H), 1.52-1.43 (m, 2H), 1.29-1.23 (m, 2H), 1.01 (t, J = 7.3Hz, 3H), 0.85-0.79 (m, 2H)

LC-MS: m / z 329.0 [M + H] ⁺ at 2.99 RT (99.92% purity)

HPLC: 99.82%

[Example 98]

[Program]

N- (2- (cyclopropylamino) -4-methylphenyl) -6-methylpyrazine-4-carboxamide

At 0 ° C, N ¹ -cyclopropyl-5-methylbenzene-1,2-diamine Int-18 (120 mg, crude) and 6-methylpyrazine-4-carboxylic acid (129 mg , 0.74 mmol) in a stirred solution of CH ₂ Cl ₂ (5 mL) was added dropwise HATU (310 mg, 0.81 mmol) and HOBt (110 mg, 0.81 mmol), followed by ethyl diisopropylamine (0.52 mL, 2.96 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (20mL) was diluted and extracted with _{CH 2 Cl 2 (2 x 20mL} ). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2- (cyclopropylamino) -4-methylbenzene as an off-white solid. ) -6-methylpyrazine-4-carboxamide (120 mg, 0.42 mmol, 57%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.80 (s, 1H), 9.48 (s, 1H), 7.99 (s, 1H), 7.02 (br d, J = 7.7Hz, 1H), 6.86 (s , 1H), 6.47 (d, J = 7.7Hz, 1H), 5.63 (brs, 1H), 2.72 (s, 3H), 2.36-2.32 (m, 1H), 2.28 (s, 3H), 0.72-0.69 ( m, 2H), 0.43-0.39 (brs, 2H)

LC-MS: m / z 282.9 [M + H] ⁺ at 2.36 RT (94.69% purity)

1-cyclopropyl-6-methyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 98)

Under an inert atmosphere, N- (2- (cyclopropylamino) -4-methylphenyl) -6-methylpyrazine-4-carboxamide (120 mg, 0.42 mmol) was added at 0 ° C. A stirred solution in CH ₂ Cl ₂ (5 mL) was added dropwise trifluoroacetic acid (0.2 mL). The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (5mL), extracted with _{CH 2 Cl 2 (2 x 20mL} ) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) followed by preparative HPLC to give 1-cyclopropyl-6-methyl-2- as an off-white solid. (6-Methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 98 (25 mg, 0.09 mmol, 22%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.68 (d, J = 1.9Hz, 1H), 7.97 (d, J = 1.9Hz, 1H), 7.70 (d, J = 8.3Hz, 1H), 7.44-7.41 (m, 1H), 7.18 (dd, J = 8.3,1.1Hz, 1H), 3.66-3.61 (m, 1H), 2.84 (s, 3H), 2.56 (s, 3H), 1.31-1.25 (m, 2H ), 0.86-0.81 (m, 2H)

LC-MS: m / z 264.9 [M + H] ⁺ at 2.26 RT (99.85% purity)

HPLC: 99.84%

[Example 99]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -3-methylpyrazine-4-carboxamide

Stir N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (100 mg, 0.72 mmol) in ethyl acetate (6 mL) under an inert atmosphere at 0 ° C. To the solution was added 3-methylpyrazine-4-carboxylic acid (132 mg, 0.72 mmol) and triethylamine (0.2 mL, 1.45 mmol) followed by propylphosphonic anhydride (50% in EtOAc, 1.15 mL, 1.81 mmol). And the reaction was allowed to stir at room temperature for 2h. After consuming the starting material (by TLC), the reaction mixture was basified using a saturated NaHCO3 solution (pH about 8) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2- (cyclopropylamino) -4,5-di Fluorophenyl) -3-methylpyrazine-4-carboxamide (100 mg, 0.33 mmol, 45%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.74 (s, 1H), 9.28 (d, J = 5.0Hz, 1H), 7.86 (d, J = 5.0Hz, 1H), 7.48 (dd, J = 11.9, 8.7Hz, 1H), 6.94 (dd, J = 13.6, 8.0Hz, 1H), 5.83 (s, 1H), 2.72 (s, 3H), 2.41-2.33 (m, 1H), 0.80-0.71 (m , 2H), 0.46-0.37 (m, 2H)

LC-MS: m / z 305.1 [M + H] ⁺ at 2.43 RT (96.65% purity)

1-cyclopropyl-5,6-difluoro-2- (3-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.99)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -3-methylpyrazine-4-carboxamide (80 mg, 0.26 mmol ) A stirred solution in ethanol (0.8 mL) was added dropwise 6N HCl (0.4 mL). Subsequently, the reaction mixture was heated to 60 ° C. and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, basified with saturated NaHCO ₃ solution (pH about 8) and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-5,6-difluoro-2- (3- pyridazin-4-yl-methyl) -1 H - benzo [d] imidazole Ex.99 (40mg, 0.14mmol, 53% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.26 (d, J = 5.1Hz, 1H), 7.63-7.55 (m, 2H), 7.42 (dd, J = 9.6, 7.0Hz, 1H), 3.41-3.36 ( m, 1H), 2.82 (s, 3H), 1.10-1.01 (m, 2H), 0.72-0.62 (m, 2H).

LC-MS: m / z 287.2 [M + H] ⁺ at 3.10 RT (98.57% purity)

HPLC: 98.53%

[Example 100]

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -3,6-dimethylpyrazine-4-carboxamide

To N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (200 mg, 1.09 mmol) in ethyl acetate (10 mL) at 0-5 ° C under an inert atmosphere. To the stirred solution was added 3,6-dimethylpyrazine-4-carboxylic acid (165 mg, 1.09 mmol) and triethylamine (0.3 mL, 2.17 mmol) followed by propylphosphonic anhydride (50% in EtOAc, 1.73 mL). , 2.71 mmol), and the mixture was stirred at room temperature for 2 h. After consumption of the starting material (by TLC), the reaction mixture was extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The material was combined with another batch (100 mg, crude material) and purified by silica gel column chromatography (eluent: 2% MeOH / EtOAc) to give N- (2- (cyclopropyl) as a brown solid Amine) -4,5-difluorophenyl) -3,6-dimethylpyrazine-4-carboxamide (260 mg, 0.82 mmol, 51%).

LC-MS: m / z 319.1 [M + H] ⁺ at 2.51 RT (98.54% purity)

1-cyclopropyl-2- (3,6-dimethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 100)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -3,6-dimethylpyrazine-4-carboxamide (200 mg 6N HCl (0.4 mL) was added dropwise to a stirred solution of 0.63 mmol) in ethanol (3 mL). Subsequently, the reaction mixture was heated to 60 ° C. and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, basified with saturated NaHCO ₃ (pH about 8) and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The material was combined with another batch (50 mg, crude material) and purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to give a solid, which was triturated with EtOAc (5 mL) And below drying to give 1-cyclopropyl-2- (3,6-dimethylpyrazin-4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole as an off-white solid Ex. 100 (110 mg, 0.37 mmol, 48%).

¹ H NMR (400MHz, CD ₃ OD): δ 7.87 (s, 1H), 7.71 (dd, J = 10.1, 7.1Hz, 1H), 7.60 (dd, J = 10.4, 7.3Hz, 1H), 3.63-3.57 (m, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 1.09-1.02 (m, 2H), 0.73-0.67 (m, 2H)

LC-MS: m / z 300.9 [M + H] ⁺ at 2.35 RT (98.70% purity)

HPLC: 99.50%

[Example 101]

N- (2- (cyclopropylamino) -3,4-difluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

At 0 ° C, N ¹ -cyclopropyl-5,6-difluorobenzene-1,2-diamine Int-20 (250 mg, crude material) and 6- (difluoromethyl) Triethylamine (0.38mL, 2.72mmol) was added dropwise to a stirred solution of oxazine-4-carboxylic acid Int-29 (260mg, 1.49mmol) in ethyl acetate (5mL), followed by propylphosphonic anhydride (50% in EtOAc, 2.16 mL, 3.4 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2- (cyclopropylamino) -3,4-di Fluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (300 mg, 0.88 mmol, 65%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 9.79 (s, 1H), 8.45 (d, J = 1.2Hz, 1H), 7.56-7.28 (m, 1H), 6.95 ( t, J = 6.7 Hz, 1H), 6.68 (q, J = 8.7 Hz, 1H), 5.60 (br s, 1H), 2.82-2.75 (m, 1H), 0.63-0.48 (m, 4H)

LC-MS: m / z 340.9 [M + H] ⁺ at 2.79 RT (92.05% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6,7-difluoro-1 H -benzo [ d ] imidazole (Ex. 101)

N- (2- (cyclopropylamino) -3,4-difluorophenyl) -6- (difluoromethyl) pyridazine-4-carboxamide ( A stirred solution of 150 mg, 0.44 mmol) in ethanol (1.5 mL) was added dropwise 6 N HCl (2.25 mL). The reaction mixture was stirred in a preheated oil bath at 60 ° C for 15 min. After consuming the starting material (by TLC), the reaction mixture was cooled to 0 ° C, basified with a saturated NaHCO3 solution (pH about 8) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) to obtain 1-cyclopropyl-2- (6- (difluoromethyl) pyridazine- 4-yl) -6,7-difluoro- 1H -benzo [ d ] imidazole Ex. 101 (70 mg, 0.22 mmol, 49%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.97 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.57-7.29 ( m, 2H), 4.20-4.15 (m, 1H), 1.16-1.09 (m, 2H), 0.88-0.84 (m, 2H)

LC-MS: m / z 323.0 [M + H] ⁺ at 2.83 RT (98.57% purity)

HPLC: 98.76%

[Example 102]

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-thiol (Ex.102)

Under an inert atmosphere, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 22 ( A stirred solution of 100 mg, 0.33 mmol) in ethanol (5 mL) was added with thiourea (35 mg, 0.49 mmol). The reaction mixture was heated to reflux temperature for 4 h and cooled. A saturated sodium hydroxide solution (2 mL) was added at room temperature and heated to reflux temperature for 1 h. The reaction mixture was cooled and neutralized to pH about 7 using 6N HCl. The precipitated solid was filtered and the solid was washed again successively with water (5 mL), MeOH (5 mL), CH ₂ Cl ₂ (5 mL), EtOAc (5 mL), Et ₂ O (5 mL) to give 5- (1- Cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazine-3-thiol Ex. 102 (50 mg, 0.16 mmol, 50%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 14.94 (br s, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 7.89-7.80 (m, 2H), 3.93 -3.83 (m, 1H), 1.22-1.19 (m, 2H), 0.91-0.89 (m, 2H)

LC-MS: m / z 304.9 [M + H] ⁺ at 2.56 RT (94.69% purity)

HPLC: 93.13%

[Example 103]

N- (2-amino-4,5-difluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

To a stirred solution of 4,5-difluorobenzene-1,2-diamine Int-12 (199 mg, 1.37 mmol) in EtOAc (12 mL) was added 6- (difluoromethyl) at 0 ° C under an inert atmosphere. ) Triazine-4-carboxylic acid Int-29 (200 mg, 1.14 mmol), triethylamine (0.32 mL, 2.29 mmol), and propylphosphonic anhydride (50% in EtOAc, 1.83 mL, 2.87 mmol). The reaction mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC & LC-MS), the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (70 mL) and brine (70mL), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to obtain N- (2-amino-4,5-difluorophenyl) -6- as a yellow solid. (Difluoromethyl) pyrazine-4-carboxamide (70 mg, 0.23 mmol, 13%).

LC-MS: m / z 300.9 [M + H] ⁺ at 2.2 RT (85.12% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 103)

Under an inert atmosphere, N- (2-amino-4,5-difluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (50 mg, 0.16 mmol) was added at room temperature. To the stirred solution in EtOH (0.75 mL) was added 6 N HCl (0.5 mL). The reaction mixture was heated to 90 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl) -5 as a pink solid. , 6-difluoro- 1H -benzo [ d ] imidazole Ex. 103 (15 mg, 0.05 mmol, 23%).

¹ H NMR (400 MHz, DMSO- d ₆ ) : δ 13.88 (brs, 1H), 10.03 (d, J = 2.0 Hz, 1 H), 8.58 (d, J = 2.1 Hz, 1 H), 7.87-7.81 (m, 2H), 7.55-7.25 (m, 1H)

LC-MS: m / z 283.1 [M + H] ⁺ at 2.12 RT (97.58% purity)

HPLC: 98.71%

[Example 104]

N- (4,5-difluoro-2- (methylamino) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

At 0 ° C, 4,5-difluoro- N ¹ -methylbenzene-1,2-diamine Int-15 (200 mg, crude substance) and 6- (difluoromethyl) pyridazine A stirred solution of 4-carboxylic acid Int-29 (220 mg, 1.26 mmol) in ethyl acetate (20 mL) was added dropwise triethylamine (0.38 mL, 2.53 mmol) and propylphosphonic anhydride (50% in EtOAc, 2 mL). , 3.16 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give N- (4,5-difluoro-2- (methylamino) benzene as a pale yellow solid. ) -6- (difluoromethyl) pyridazine-4-carboxamide (210 mg, 0.67 mmol, 53%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.23 (s, 1H), 9.81 (d, J = 1.7Hz, 1H), 8.48 (d, J = 1.7Hz, 1H), 7.55-7.25 (m, 2H), 6.60 (dd, J = 13.6, 7.8Hz, 1H), 5.68 (br s, 1H), 2.69 (d, J = 4.6Hz, 3H)

LC-MS: m / z 314.9 [M + H] ⁺ at 2.53 RT (93.02% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1-methyl-1 H -benzo [ d ] imidazole (Ex.104)

N- (4,5-difluoro-2- (methylamino) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (150 mg , 0.48 mmol) in a stirred solution of ethanol (1.5 mL) was added 6 N HCl (1.5 mL). Subsequently, the reaction mixture was stirred in a preheated oil bath at 80 ° C. for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl)-as a pale yellow solid. 5 6-difluoro-1-methyl-1 H -benzo [ d ] imidazole Ex. 104 (98 mg, 0.33 mmol, 69%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.89 (s, 1H), 8.44 (d, J = 1.7Hz, 1H), 7.99 (dd, J = 10.4,7.5Hz, 1H), 7.89 (dd, J = 11.0, 7.5Hz, 1H), 7.54-7.29 (m, 1H), 4.04 (s, 3H)

LC-MS: m / z 296.9 [M + H] ⁺ at 2.46 RT (97.61% purity)

HPLC: 97.08%

[Example 105]

N- (4,5-difluoro-2- (propylamino) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

At 0 ° C, 4,5-difluoro- N ¹ -propylbenzene-1,2-diamine Int-16 (200 mg, crude substance) and 6- (difluoromethyl) pyridazine A stirred solution of 4-carboxylic acid Int-29 (187 mg, 1.07 mmol) in ethyl acetate (20 mL) was added dropwise triethylamine (0.3 mL, 2.15 mmol) and propylphosphonic anhydride (50% in EtOAc, 1.71). mL, 2.69 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give N- (4,5-difluoro-2- (propylamino) phenyl) as a yellow solid. ) -6- (difluoromethyl) pyrazine-4-carboxamide (200 mg, 0.58 mmol, 55%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.19 (brs, 1H), 9.82 (d, J = 1.2Hz, 1H), 8.47 (d, J = 1.7Hz, 1H), 7.55-7.23 (m, 2H), 6.66 (dd, J = 13.9, 7.5Hz, 1H), 5.52 (brs, 1H), 3.02 (q, J = 6.6Hz, 2H), 1.60-1.50 (m, 2H), 0.91 (t, J = 7.5Hz, 3H)

LC-MS: m / z 342.9 [M + H] ⁺ at 3.00 RT (95.46% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1-propyl-1 H -benzo [ d ] imidazole (Ex. 105)

N- (4,5-difluoro-2- (propylamino) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (150 mg , 0.44 mmol) in a stirred solution of ethanol (1.5 mL) was added 6 N HCl (1.5 mL). Subsequently, the reaction mixture was stirred in a preheated oil bath at 80 ° C. for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl) -5 as a yellow solid. , 6-difluoro-1-propyl- 1H -benzo [ d ] imidazole Ex. 105 (110 mg, 0.34 mmol, 77%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.85 (d, J = 1.7Hz, 1H), 8.38 (d, J = 1.7Hz, 1H), 8.07 (dd, J = 10.7,7.2Hz, 1H) , 7.89 (dd, J = 11.0, 7.5Hz, 1H), 7.53-7.28 (m, 1H), 4.42 (t, J = 7.2Hz, 2H), 1.75-1.68 (m, 2H), 0.77 (t, J = 7.2Hz, 3H)

LC-MS: m / z 324.9 [M + H] ⁺ at 2.90 RT (97.45% purity)

HPLC: 96.79%

[Example 106]

Diethyl 2-hydroxy-2- (2- pendant oxycyclohexyl) malonate

In a sealed tube, a solution of diethyl 2-oxomalonate (500 mg, 2.87 mmol) and cyclohexanone (282 mg, 2.87 mmol) was heated to 100 ° C and stirred for 16 h and cooled. The reaction mixture (brown slurry) (500 mg) containing diethyl 2-hydroxy-2- (2- pendant oxycyclohexyl) malonate (500 mg) was used in the next step without further purification.

LC-MS: m / z 273.3 [M + H] ⁺ at 2.83 RT (82.91% purity)

3-Hydroxy-5,6,7,8-tetrahydrophospholine-4-carboxylic acid ethyl ester

To a stirred solution of 2-hydroxy-2- (2- pendant oxycyclohexyl) malonate (5 g, crude material) in acetic acid (35 mL) at room temperature, add a hydrazine mono salt Acid salt (6.25 g, 91.91 mmol). The reaction mixture was heated to 100 ° C and stirred for 3 h. Monitoring the progress of the reaction by TLC, the reaction mixture with saturated NaHCO ₃ solution (100 mL) quenched and extracted with EtOAc (2 x 60mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 3-hydroxy-5,6,7,8-tetrahydropyridin-4 as an off-white solid. -Ethyl formate (4 g, 18.0 mmol, 98%).

¹ H NMR (500MHz, CDCl ₃ ): δ 4.48 (q, J = 7.1Hz, 2H), 3.18 (t, J = 6.4Hz, 2H), 2.81 (t, J = 6.4Hz, 2H), 1.99-1.92 (m, 2H), 1.89-1.82 (m, 2H), 1.44 (t, J = 7.2Hz, 3H)

LC-MS: m / z 223.0 [M + H] ⁺ at 1.87 RT (83.82% purity)

3-Chloro-5,6,7,8-tetrahydrophospholine-4-carboxylic acid ethyl ester

In a sealed tube, ethyl 3-hydroxy-5,6,7,8-tetrahydropyridin-4-carboxylate (4 g, 18.0 mmol) was added to 1,4-dioxane at room temperature under an inert atmosphere. A stirred solution in alkane (40 mL) was added phosphorophosphonium chloride (16.79 mL, 179.98 mmol) to heat the reaction mixture to 100 ° C and stirred for 2 h. Monitoring the progress of the reaction by TLC, the reaction mixture with saturated NaHCO ₃ solution (100 mL) quenched and extracted with EtOAc (2 x 60mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 3-chloro-5,6,7,8-tetrahydropyridine-4-carboxylic acid as a brown solid. Ethyl ester (3.5 g, 14.54 mmol, 81%).

¹ H NMR (500MHz, CDCl ₃ ): δ 4.48 (q, J = 7.0Hz, 2H), 3.17 (t, J = 6.4Hz, 2H), 2.80 (t, J = 6.7Hz, 2H), 1.98-1.92 (m, 2H), 1.88-1.82 (m, 2H), 1.43 (t, J = 7.0Hz, 3H)

LC-MS: m / z 241.0 [M + H] ⁺ at 2.57 RT (99.53% purity)

Ethyl 5,6,7,8-tetrahydrophosphino-4-carboxylic acid

To a stirred solution of ethyl 3-chloro-5,6,7,8-tetrahydrophospholine-4-carboxylate (500 mg, 2.08 mmol) in ethyl acetate (10 mL) at room temperature under an inert atmosphere was added. 10% Pd / C (50% wet, 150 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 1 h. The progress of the reaction was monitored by TLC, the reaction mixture was filtered through a celite pad and the bed was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give a brown slurry of 5,6,7,8-tetrahydrophospholine-4-carboxylic acid ethyl ester (100 mg , 0.48 mmol, 23%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.26 (s, 1H), 4.41 (q, J = 7.2Hz, 2H), 3.22 (t, J = 6.5Hz, 2H), 3.15 (t, J = 6.5Hz , 2H), 1.98-1.89 (m, 2H), 1.89-1.80 (m, 2H), 1.41 (t, J = 7.2Hz, 3H)

LC-MS: m / z 206.9 [M + H] ⁺ at 2.12 RT (98.29% purity)

5,6,7,8-tetrahydrophospholine-4-carboxylic acid

To a stirred solution of ethyl 5,6,7,8-tetrahydrophospholine-4-carboxylic acid (20 mg, 0.1 mmol) in a mixture of THF / water (4: 1, 1 mL) at room temperature was added lithium hydroxide Monohydrate (12 mg, 0.29 mmol). Subsequently, the reaction mixture was lyophilized to obtain 5,6,7,8-tetrahydrophospholine-4-carboxylic acid (25 mg, 0.14 mmol) as an off-white solid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.24 (s, 1H), 3.14 (t, J = 6.4Hz, 2H), 3.09 (t, J = 6.4Hz, 2H), 1.89-1.81 (m, 2H), 1.80-1.72 (m, 2H)

LC-MS: m / z 179.0 [M + H] ⁺ at 2.73 RT (70.16% purity)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5,6,7,8-tetrahydrofluoroline-4-carboxamide

To a stirred solution of 5,6,7,8-tetrahydrophospholine-4-carboxylic acid (86 mg, crude material) in ethyl acetate (5 mL) at 0 ° C. under an inert atmosphere was added N ¹ -cyclopropyl -4,5-difluorobenzene-1,2-diamine Int-5 (88mg, 0.48mmol), triethylamine (0.27mL, 1.93mmol) and propylphosphonic anhydride (50% in EtOAc, 0.77mL, 1.21 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. Monitoring the progress of the reaction by TLC, the reaction mixture with saturated NaHCO ₃ solution (20mL) was quenched and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2- (cyclopropylamino) -4,5-di Fluorophenyl) -5,6,7,8-tetrahydropyridin-4-carboxamide (50 mg, 0.14 mmol, 30%).

LC-MS: m / z 343.1 [MH] - in 2.74 RT (66.07% purity)

4- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -5,6,7,8-tetrahydrofluoroline (Ex.106)

To N- (2- (cyclopropylamino) -4,5-difluorophenyl) -5,6,7,8-tetrahydropyridin-4-carboxamidine at room temperature under an inert atmosphere A stirred solution of amine (50 mg, 0.14 mmol) in ethanol (0.5 mL) was added dropwise 6 N HCl (0.2 mL). Subsequently, the reaction mixture was heated to 60 ° C. and stirred for 2 h. The reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 4- (1-cyclopropyl-5,6-difluoro-1 H ) as an off-white solid. -Benzo [ d ] imidazol-2-yl) -5,6,7,8-tetrahydroxanthroline Ex. 106 (20 mg, 0.06 mmol, 42%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.20 (s, 1H), 7.71 (dd, J = 10.1, 7.1Hz, 1H), 7.60 (dd, J = 10.4, 7.3Hz, 1H), 3.65-3.60 (m, 1H), 3.24 (t, J = 6.6Hz, 2H), 2.90 (t, J = 6.4Hz, 2H), 2.07-1.99 (m, 2H), 1.90-1.82 (m, 2H), 1.08- 1.02 (m, 2H), 0.73-0.67 (m, 2H)

LC-MS: m / z 327.2 [M + H] ⁺ at 2.22 RT (95.90% purity)

HPLC: 96.28%

[Example 107]

N- (5-cyano-2- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide

Add 3-amino-4- (cyclopropylamino) benzonitrile Int-22 (198 mg, crude) and 6-methylpyrazine-4-carboxylic acid hydrochloride under an inert atmosphere at 0 ° C. A stirred solution of salt (200 mg, 1.15 mmol) in ethyl acetate (12 mL) was added dropwise triethylamine (0.39 mL, 2.29 mmol), followed by propylphosphonic anhydride (50% in EtOAc, 1.82 mL, 2.86 mmol). The reaction was warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 60% EtOAc / hexane) to give N- (5-cyano-2- (cyclopropylamino) phenyl) as a pale yellow solid. ) -6-methylpyrazine-4-carboxamide (400 mg, 1.34 mmol, 79%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.12 (s, 1H), 9.60 (d, J = 2.0Hz, 1H), 8.11 (d, J = 2.0Hz, 1H), 7.71-7.63 (m, 2H), 7.19 (d, J = 8.5Hz, 1H), 6.83 (s, 1H), 2.84 (s, 3H), 2.57-2.50 (m, 1H), 0.92-0.85 (m, 2H), 0.60-0.55 (m, 2H)

LC-MS: m / z 293.9 [M + H] ⁺ at 2.14 RT (88.98% purity)

1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-5-carbonitrile (Ex.107)

At room temperature, N- (5-cyano-2- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide (200 mg, 0.68 mmol) was added to A stirred solution in ethanol (2 mL) was added dropwise 6 N HCl (3 mL). Subsequently, the reaction mixture was stirred in a preheated oil bath at 70 ° C for 25 min. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, pH of about 8 and extracted with EtOAc (2 x 20mL) and basified with saturated NaHCO ₃ solution to. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 1-2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6-methylpyrazine- 4- yl) -1 H - benzo [d] imidazole-5-carbonitrile Ex.107 (120mg, 0.43mmol, 64% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.69 (s, 1H), 8.16 (dd, J = 1.4, 0.6Hz, 1H), 7.98 (d, J = 1.9Hz, 1H), 7.75 (dd, J = 8.4, 0.6Hz, 1H), 7.65 (dd, J = 8.4, 1.5Hz, 1H), 3.74-3.69 (m, 1H), 2.88 (s, 3H), 1.38-1.32 (m, 2H), 0.89-0.83 (m, 2H)

LC-MS: m / z 275.9 [M + H] ⁺ at 2.07 RT (99.17% purity)

HPLC: 99.01%

[Example 108]

N- (2- (cyclobutylamino) -4,5-difluorophenyl) -6-methylpyrazine-4-carboxamide

At 0 ° C, N ¹ -cyclobutyl-4,5-difluorobenzene-1,2-diamine Int-21 (200 mg, crude material) and 6-methylpyrazine-4- A stirred solution of formate salt (176 mg, 1.01 mmol) in ethyl acetate (10 mL) was added dropwise triethylamine (0.56 mL, 4.04 mmol), followed by propylphosphonic anhydride (50% in EtOAc, 1.61 mL, 2.52 mmol). The reaction was warmed to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2- (cyclobutylamino) -4,5-di Fluorophenyl) -6-methylpyrazine-4-carboxamide (250 mg, 0.78 mmol, 78%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.95 (s, 1H), 9.51 (s, 1H), 8.01 (s, 1H), 7.31 (dd, J = 11.5, 8.8Hz, 1H), 6.54 ( dd, J = 13.7, 7.7Hz, 1H), 5.58 (d, J = 6.6Hz, 1H), 3.91-3.79 (m, 1H), 2.74 (s, 3H), 2.40-2.31 (m, 2H), 1.93 -1.83 (m, 2H), 1.76-1.66 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.64 RT (97.50% purity)

1-cyclobutyl-5,6-difluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.108)

N- (2- (cyclobutylamino) -4,5-difluorophenyl) -6-methylpyrazine-4-carboxamide (150 mg, 0.47 mmol ) A stirring solution in ethanol (1.5 mL) was added dropwise 6N HCl (2.2 mL). The reaction mixture was heated to 60 ° C. for 15 min in a pre-heated oil bath and cooled. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclobutyl-5,6-difluoro-2- (6- pyridazin-4-yl-methyl) -1 H - benzo [d] imidazole Ex.108 (100mg, 0.33mmol, 70% ).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.36 (d, J = 1.1Hz, 1H), 7.98 (dd, J = 11.0, 7.7Hz, 1H), 7.88-7.80 (m, 2H), 5.19- 5.12 (m, 1H), 2.74 (s, 3H), 2.44-2.42 (m, 4H), 1.89-1.70 (m, 2H).

LC-MS: m / z 300.9 [M + H] ⁺ at 2.51 RT (98.06% purity)

HPLC: 98.42%

[Example 109]

N- (2- (cyclopropylamino) -4-hydroxyphenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

4-amino-3- (cyclopropylamino) phenol Int-17 (50 mg, crude) and 6- (difluoromethyl) pyrazine-4-carboxylic acid Int at 0 ° C under an inert atmosphere A stirred solution of -29 (53mg, 0.3mmol) in ethyl acetate (10mL) was added dropwise triethylamine (0.08mL, 0.61mmol) and propylphosphonic anhydride (50% in EtOAc, 0.48mL, 0.76mmol) . After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, pH of about 8 and extracted with EtOAc (2 x 20mL) and basified with saturated NaHCO ₃ solution to. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give N- (2- (cyclopropylamino) -4-hydroxyphenyl) as a pale yellow solid. -6- (difluoromethyl) pyridazine-4-carboxamide (50 mg, 0.16 mmol, 51%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.88 (s, 1H), 9.80 (s, 1H), 9.16 (br s, 1H), 8.44 (s, 1H), 7.55-7.26 (m, 1H) , 6.89 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 1.7 Hz, 1H), 6.07 (dd, J = 8.4, 2.0 Hz, 1H), 5.71 (s, 1H), 2.30-2.28 ( m, 1H), 0.71-0.68 (m, 2H), 0.43-0.39 (m, 2H)

LC-MS: m / z 321.2 [M + H] ⁺ at 1.84 RT (99.05% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-ol (Ex.109)

N- (2- (cyclopropylamino) -4-hydroxyphenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (50 mg, 0.16 A stirred solution of mmol) in ethanol (1 mL) was added dropwise 6 N HCl (1 mL). The reaction mixture was heated to 70 ° C. for 1 h in a pre-heated oil bath. After consuming the starting material (by TLC), the reaction mixture was cooled to 0 ° C, basified using a saturated NaHCO3 solution (pH about 8) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (difluoromethyl) pyridazine- 4- yl) -1 H - benzo [d] imidazol-6-ol Ex.109 (40mg, 0.13mmol, 85% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.93 (d, J = 2.1Hz, 1H), 8.54 (d, J = 2.1Hz, 1H), 7.57 (d, J = 8.8Hz, 1H), 7.29- 7.00 (m, 2H), 6.90 (dd, J = 8.8, 2.3 Hz, 1H), 3.88-3.82 (m, 1H), 1.31-1.22 (m, 2H), 0.86-0.79 (m, 2H)

LC-MS: m / z 302.9 [M + H] ⁺ at 2.01 RT (99.11% purity)

HPLC: 98.91%

[Example 110]

5- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester

In a steel high-pressure tank, at room temperature toward 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1H-benzo [d] imidazole Ex. 22 (1 g, 2.9 mmol) in a stirred solution of methanol (50 mL) was added sodium acetate (713 mg, 8.69 mmol) and dppf (80 mg, 0.14 mmol) followed by Pd (OAc) ₂ (97 mg, 0.14 mmol). The steel high-pressure tank was filled with CO gas (200 psi) and the reaction mixture was heated to 100 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 5- (1-cyclopropyl-5,6-difluoro-1H- Benzo [d] imidazol-2-yl) pyridazin-3-carboxylic acid methyl ester (200 mg, 0.6 mmol, 21%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.03 (d, J = 2.1Hz, 1H), 8.73 (d, J = 2.1Hz, 1H), 7.93-7.84 (m, 2H), 4.03 (s, 3H), 4.00-3.96 (m, 1H), 1.23-1.16 (m, 2H), 0.84-0.78 (m, 2H)

LC-MS: m / z 330.9 [M + H] ⁺ at 2.49 RT (94.38% purity)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid (Ex.110)

To 5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) at 0 ° C at A stirred solution of a mixture of THF / water (3: 1, 3 mL) was added lithium hydroxide monohydrate (38 mg, 0.91 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The reaction mixture was washed with diethyl ether (10 mL) and the organic layer was separated. The aqueous layer was acidified with concentrated HCl (pH about 2), resulting in the formation of a precipitate. The precipitated solid was filtered, washed with diethyl ether (2 x 5 mL) and dried under vacuum to give 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole- 2-yl) pyridazin-3-carboxylic acid Ex. 110 (40 mg, 0.13 mmol, 42%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 14.15 (brs, 1H), 10.00 (d, J = 2.1Hz, 1H), 8.72 (d, J = 2.1Hz, 1H), 7.93-7.84 (m, 2H), 4.00-3.95 (m, 1H), 1.22-1.16 (m, 2H), 0.83-0.78 (m, 2H)

LC-MS: m / z 316.9 [M + H] ⁺ at 1.55 RT (99.76% purity)

HPLC: 99.88%

[Example 111]

N- (2- (cyclopropylamino) -3-fluorophenyl) -6-methylpyrazine-4-carboxamide

To N ¹ -cyclopropyl-6-fluorobenzene-1,2-diamine Int-14 (100 mg, crude substance) and 6-methylpyrazine-4-formate at 0 ° C under an inert atmosphere. A stirred solution of the acid salt (83 mg, 0.6 mmol) in ethyl acetate (4 mL) was added triethylamine (0.34 mL, 2.41 mmol) and propylphosphonic anhydride (50% in EtOAc, 0.95 mL, 1.51 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture with saturated NaHCO ₃ solution (20mL) and quenched extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give N- (2- (cyclopropylamino) -3-fluorophenyl)-as an off-white solid. 6-methylpyrazine-4-carboxamide (200 mg, 0.7 mmol, 72%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.06 (br s, 1H), 9.47 (s, 1H), 7.98 (s, 1H), 7.05-6.97 (m, 2H), 6.73-6.66 (m, 1H), 5.09 (br s, 1H), 2.72-2.70 (m, 4H), 0.55-0.42 (m, 4H)

LC-MS: m / z 286.9 [M + H] ⁺ at 2.15 RT (91.92% purity)

1-cyclopropyl-7-fluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.111)

To N- (2- (cyclopropylamino) -3-fluorophenyl) -6-methylpyrazine-4-carboxamide (200 mg, 0.7 mmol) in ethanol under an inert atmosphere at room temperature To the stirred solution (3 mL) was added 6 N HCl (2 mL). Subsequently, the reaction mixture was stirred in a preheated oil bath at 65 ° C for 15 min. After consumption of the starting material (by TLC), the reaction mixture was quenched with saturated NaHCO ₃ solution (30mL) and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH ₂ Cl ₂ ), followed by washing with n-pentane (2 x 5 mL) and drying in vacuo to give 1 as an off-white solid. -Cyclopropyl -7-fluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 111 (110 mg, 0.41 mmol, 59%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.64 (d, J = 1.7Hz, 1H), 8.14 (d, J = 2.0Hz, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.30 -7.17 (m, 2H), 4.11-4.07 (m, 1H), 2.77 (s, 3H), 1.15-1.10 (m, 2H), 0.77-0.75 (m, 2H)

LC-MS: m / z 269.2 [M + H] ⁺ at 2.05 RT (98.96% purity)

HPLC: 98.50%

[Example 112]

N- (5-chloro-2- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide

To a stirred solution of 4-chloro- N ¹ -cyclopropylbenzene-1,2-diamine Int-24 (200mg, crude) in ethyl acetate (8mL) was added dropwise at 0 ° C under an inert atmosphere. 6-methylpyrazine-4-formate (191 mg, 1.1 mmol) and triethylamine (0.61 mL, 4.37 mmol), followed by propylphosphonic anhydride (50% in EtOAc, 1.74 mL, 2.73 mmol). The reaction was allowed to stir at room temperature for 4 h. After consumption of the starting material (by TLC), the reaction mixture was extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. This batch was combined with another batch (90 mg of crude material) and purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give N- (5-chloro- 2- (Cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide (200 mg, 0.66 mmol, 40%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.94 (s, 1H), 9.49 (d, J = 1.7Hz, 1H), 8.00 (d, J = 1.9Hz, 1H), 7.26 (d, J = 2.3Hz, 1H), 7.19 (dd, J = 8.7, 2.5Hz, 1H), 7.03 (d, J = 8.7Hz, 1H), 5.93 (s, 1H), 2.73 (s, 3H), 2.38-2.32 ( m, 1H), 0.75-0.70 (m, 2H), 0.45-0.40 (m, 2H)

LC-MS: m / z 302.9 [M + H] ⁺ at 2.55 RT (88.67% purity)

5-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 112)

N- (5-chloro-2- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide (100 mg, 0.33 mmol) in ethanol at room temperature under an inert atmosphere (1 mL) in the stirred solution was added dropwise 6 N HCl (1mL). The reaction mixture was heated to 50 ° C. for 1 h with a pre-heated oil bath, cooled to 0 ° C., basified with a saturated NaHCO ₃ solution (pH about 8) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. This batch was combined with another batch (90 mg, crude material) and purified by silica gel column chromatography (eluent: 70-80% EtOAc / hexane) to give 5-chloro- as an off-white solid 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 112 (100 mg, 0.35 mmol, 53%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.66 (d, J = 2.0Hz, 1H), 8.17 (d, J = 1.9Hz, 1H), 7.84 (d, J = 1.9Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.42 (dd, J = 8.6, 2.0Hz, 1H), 3.96-3.92 (m, 1H), 2.77 (s, 3H), 1.22-1.17 (m, 2H), 0.77-0.72 (m, 2H)

LC-MS: m / z 284.9 [M + H] ⁺ at 2.42 RT (96.67% purity)

HPLC: 96.19%

[Example 113]

N- (2-chloro-6- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide

To a stirred solution of 3-chloro- N ¹ -cyclopropylbenzene-1,2-diamine Int-25 (200 mg, crude material) in ethyl acetate (10 mL) at 0 ° C was added 6 -Methylpyrazine-4-formate (191 mg, 1.1 mmol) and triethylamine (0.31 mL, 2.2 mmol), followed by propylphosphonic anhydride (50% in EtOAc, 1.75 mL, 2.75 mmol ), And the reaction was allowed to stir at room temperature for 2 h. After consumption of the starting material (by TLC), the reaction mixture was extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain N- (2-chloro-6- (cyclopropylamino) phenyl) as an off-white solid. ) -6-methylpyrazine-4-carboxamide (50 mg, 0.16 mmol, 15%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.98 (s, 1H), 9.51 (d, J = 1.9Hz, 1H), 8.01 (d, J = 2.0Hz, 1H), 7.19 (t, J = 8.1Hz, 1H), 6.97 (dd , J = 8.3,0.9Hz, 1H), 6.75 (dd, J = 8.0,1.0Hz, 1H), 6.16 (s, 1H), 2.74 (s, 3H), 2.35- 2.31 (m, 1H), 0.75-0.70 (m, 2H), 0.44-0.40 (m, 2H)

LC-MS: m / z 302.9 [M + H] ⁺ at 2.38 RT (88.61% purity)

4-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 113)

N- (2-chloro-6- (cyclopropylamino) phenyl) -6-methylpyrazine-4-carboxamide (50 mg, 0.16 mmol) in ethanol at room temperature under an inert atmosphere (0.7 mL) of the stirred solution was added dropwise 6N HCl (0.3 mL). Subsequently, the reaction mixture was heated to 60 ° C and stirred for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, basified with saturated NaHCO ₃ solution (pH about 8) and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70-80% EtOAc / hexanes) to give 4-chloro-1-cyclopropyl-2- (6-methyl-da-methyl) as an off-white solid. oxazin-4-yl) -1 H - benzo [d] imidazole Ex.113 (30mg, 0.1mmol, 64% ).

¹ H NMR (400MHz, CD ₃ OD): δ 9.67 (d, J = 2.0Hz, 1H), 8.24 (d, J = 2.1Hz, 1H), 7.75-7.71 (m, 1H), 7.39 (dd, J = 4.6, 0.8Hz, 2H), 3.91-3.86 (m, 1H), 2.84 (s, 3H), 1.29-1.23 (m, 2H), 0.84-0.79 (m, 2H)

LC-MS: m / z 285.1 [M + H] ⁺ at 2.07 RT (95.04% purity)

HPLC: 95.53%

[Example 114]

(5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol

At 0 ° C, 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-carboxaldehyde Int-27 ( 400 mg, crude material) in a stirred solution of methanol (20 mL) was added sodium borohydride (25 mg, 0.67 mmol) and the reaction was stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with 5% CH ₂ Cl ₂ / n-pentane (10 mL) to give 5- (1-cyclopropyl-5,6-difluoro-1H-benzo [d] imidazole-2 as an off-white solid. -Yl) pyridazin-3-yl) methanol (300 mg, 1.0 mmol, 75%).

LC-MS: m / z 302.9 [M + H] ⁺ at 2.10 RT (90.22% purity)

1-cyclopropyl-5,6-difluoro-2- (6- (methoxymethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 114)

At 0 ° C, 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methanol (150 mg , 0.5 mmol) in a stirred solution of DMF (5 mL) was added sodium hydride (55% in mineral oil, 32 mg, 0.74 mmol) and the mixture was stirred for 15 min. Iodomethane (0.05 mL, 0.74 mmol) was added at 0 ° C and the reaction was stirred at room temperature for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2- (6- (formaldehyde) as an off-white solid. oxymethyl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.114 (70mg, 0.22mmol, 49% ).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.77 (d, J = 1.7Hz, 1H), 8.25 (d, J = 1.7Hz, 1H), 7.91-7.81 (m, 2H), 4.84 (s, 2H), 3.96-3.92 (m, 1H), 3.44 (s, 3H), 1.21-1.16 (m, 2H), 0.80-0.75 (m, 2H)

LC-MS: m / z 316.9 [M + H] ⁺ at 2.41 RT (96.55% purity)

HPLC: 97.19%

[Example 115]

5- (6-cyano-1-cyclopropyl-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (Ex.115)

In a steel high-pressure tank, 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile Ex.34 ( 200mg, 0.68mmol) was stirred in methanol (10 mL) was added a solution of the triethylamine (0.19mL, 1.35 mmol) and _{Pd (dppf) Cl 2 (99mg} , 0.13mmol). The steel high-pressure tank was filled with CO gas (50 psi) and the reaction mixture was heated to 60 ° C. and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ), followed by CH ₂ Cl ₂ (1 mL), Et ₂ O (1 mL), and n-pentane (2 x 5 mL) were triturated and finally dried under vacuum to give 5- (6-cyano-1-cyclopropyl-1 H -benzo [ d ] imidazole as an off-white solid. Methyl-2-yl) pyrazine-3-carboxylic acid Ex. 115 (140 mg, 0.44 mmol, 65%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.07 (d, J = 2.1Hz, 1H), 8.78 (d, J = 2.1Hz, 1H), 8.36-8.34 (m, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.73 (dd, J = 8.4,1.5Hz, 1H), 4.05-3.99 (m, 4H), 1.24-1.20 (m, 2H), 0.87-0.82 (m, 2H)

LC-MS: m / z 320.2 [M + H] ⁺ at 1.98 RT (95.55% purity)

HPLC: 95.69%

[Example 116]

5- (6-cyano-1-cyclopropyl-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid (Ex. 116)

To methyl 5- (6-cyano-1-cyclopropyl-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid Ex. 115 (80 mg, 0.25 mmol) at 0 ° C To a stirred solution of a mixture of THF / water (3: 1, 3 mL) was added lithium hydroxide monohydrate (31 mg, 0.75 mmol). The reaction mixture was converted into a clear solution. After 15-20 min., The reaction mixture was turned cloudy and stirred for 1 h at 0 ° C. The reaction mixture was washed with diethyl ether (10 mL) and the organic layer was separated. The aqueous layer was acidified with 6 N HCl (pH about 2) at 0 ° C to obtain a precipitated solid, which was filtered, washed successively with diethyl ether (2 x 5 mL) and n-pentane (2 x 5 mL) and vacuumed Dry to give 5- (6-cyano-1-cyclopropyl-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid Ex.116 (29 mg, 0.09 mmol, 38%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 14.18 (br s, 1H), 10.04 (d, J = 2.1Hz, 1H), 8.77 (d, J = 2.1Hz, 1H), 8.35-8.33 (m , 1H), 7.97 (d, J = 8.4Hz, 1H), 7.73 (dd, J = 8.4,1.5Hz, 1H), 4.05-3.98 (m, 1H), 1.25-1.18 (m, 2H), 0.87- 0.82 (m, 2H)

LC-MS: m / z 306.2 [M + H] ⁺ at 1.75 RT (99.32% purity)

HPLC: 98.53%

[Example 117]

1-cyclopropyl-2- (6- (cyclopropylmethoxy) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.117)

To a stirred solution of cyclopropylmethanol (0.11 mL, 0.98 mmol) in DMF (3 mL) at 0 ° C was added sodium hydride (60% in mineral oil, 59 mg, 1.47 mmol) and the mixture was stirred. 30min. 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazole Ex. 22 (300 mg, 0.98 mmol) was added at 0 ° C And the reaction was stirred at the same temperature for 2h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane), followed by trituration with n-pentane (2 x 10 mL) and drying in vacuo to give the 1-ring as an off-white solid. Propyl-2- (6- (cyclopropylmethoxy) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex.117 (200mg, 0.58mmol , 60 %).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.41 (d, J = 1.7Hz, 1H), 7.89-7.81 (m, 2H), 7.77 (d, J = 1.8Hz, 1H), 4.37 (d, J = 7.2Hz, 2H), 3.95-3.90 (m, 1H), 1.42-1.30 (m, 1H), 1.21-1.13 (m, 2H), 0.80-0.73 (m, 2H), 0.65-0.59 (m, 2H), 0.44-0.39 (m, 2H)

LC-MS: m / z 343.0 [M + H] ⁺ at 3.07 RT (96.81% purity)

HPLC: 97.26%

[Example 118]

1-cyclopropyl-2- (6- (2,2,2-trifluoroethoxy) pyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.118 )

To a stirred solution of 2,2,2-trifluoroethan-1-ol (66 mg, 0.68 mmol) in DMF (2 mL) at 0 ° C was added sodium hydride (60% in mineral oil, 41 mg). , 1.02 mmol) and the mixture was stirred at the same temperature for 20 min. Add 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile Ex.34 (200mg, 0.68mmol ) to DMF at 0 ° C (1 mL) and the reaction was stirred at room temperature for 4 h. After consuming the starting material (by TLC), the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (2,2,2-trifluoro) as a white solid. ethoxy) pyridazin-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile Ex.118 (180mg, 0.5mmol, 74% ).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.58 (d, J = 1.7Hz, 1H), 8.34 (s, 1H), 8.02 (d, J = 1.7Hz, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.72 (dd, J = 8.4, 1.4Hz, 1H), 5.31 (q, J = 9.0Hz, 2H), 4.01-3.97 (m, 1H), 1.22-1.17 (m, 2H), 0.85-0.81 (m, 2H)

LC-MS: m / z 360.0 [M + H] ⁺ at 2.86 RT (95.88% purity)

HPLC: 96.79%

[Example 119]

N- (5-chloro-2- (cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

At 0 ° C, add 5-chloro- N ¹ -cyclopropyl-4-fluorobenzene-1,2-diamine Int-23 (400 mg, 2.0 mmol) in ethyl acetate (10 mL) under an inert atmosphere. The stirred solution was added with 6- (difluoromethyl) pyrazine-4-carboxylic acid Int-29 (350 mg, 2.0 mmol), triethylamine (1.11 mL, 8.0 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.18 mL, 5.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mixture with saturated NaHCO ₃ solution (20mL) and quenched extracted with EtOAc (2 x 30mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. This batch was combined with another batch (100 mg of crude material) and purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) to give N- (5-chloro- 2- (Cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (300 mg, 0.84 mmol, 34%). LC-MS: m / z 357.0 [M + H] ⁺ at 3.08 RT (60.71% purity)

6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1 H -benzo [ d ] imidazole (Ex.119)

N- (5-chloro-2- (cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) pyridazine-4-carboxamide at room temperature under an inert atmosphere (200 mg, 0.56 mmol) in a stirred solution of ethanol (2 mL) was added 6 N HCl (2 mL). The reaction mixture was stirred in a preheated oil bath at 50 ° C for 1 h. After consumption of the starting material (by TLC), the reaction mixture with saturated NaHCO ₃ solution (30mL) and quenched extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH ₂ Cl ₂ ) to obtain 6-chloro-1-cyclopropyl-2- (6- (difluoro) as an off-white solid. Methyl) pyridazin-4-yl) -5-fluoro- 1H -benzo [ d ] imidazole Ex. 119 (100 mg, 0.29 mmol, 53%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.00 (d, J = 2.0Hz, 1H), 8.56 (d, J = 2.1Hz, 1H), 8.00 (d, J = 6.7Hz, 1H), 7.89 (d, J = 9.8Hz, 1H), 7.58-7.28 (m, 1H), 4.02-3.96 (m, 1H), 1.23-1.16 (m, 2H), 0.84-0.78 (m, 2H)

LC-MS: m / z 339.2 [M + H] ⁺ at 3.72 RT (94.81% purity)

HPLC: 95.18%

[Example 120]

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.120)

In a microwave container, 6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1 H -benzo [ d ] A stirred solution of imidazole Ex. 119 (150 mg, 0.44 mmol) in DMF (1 mL) was added zinc cyanide (104 mg, 0.89 mmol), and the mixture was washed under argon for 20 min. Pd ₂ (dba) ₃ (41 mg, 0.04 mmol) and Pd (dppf) Cl ₂ (33 mg, 0.04 mmol) were added and the mixture was flushed with argon for 5 min. The reaction mixture was heated to 150 ° C and stirred for 3 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the bed was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (difluoromethyl) pyridazine- 4-yl) -5-fluoro- 1H -benzo [ d ] imidazole-6-carbonitrile Ex. 120 (50 mg, 0.15 mmol, 34%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.02 (d, J = 2.0Hz, 1H), 8.59 (d, J = 2.0Hz, 1H), 8.47 (d, J = 5.6Hz, 1H), 7.98 (d, J = 10.0Hz, 1H), 7.60-7.31 (m, 1H), 4.05-4.00 (m, 1H), 1.23-1.16 (m, 2H), 0.87-0.82 (m, 2H)

LC-MS: m / z 329.9 [M + H] ⁺ at 2.67 RT (99.00% purity)

HPLC: 98.49%

[Example 121]

[Program]

Diethyl 2-hydroxy-2- (2- pendant oxycyclopentyl) malonate

In a sealed tube, a solution of diethyl 2-oxomalonate (5 g, 28.73 mmol) and cyclopentanone (2.54 mL, 28.73 mmol) was heated to 100 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture (brown slurry) (5 g) containing diethyl 2-hydroxy-2- (2- pendant oxycyclopentyl) malonate (5 g) was used without further purification Adopted in the next step.

LC-MS: m / z 259.0 [M + H] ⁺ at 2.05 RT (47.02% purity)

3-hydroxy-6,7-dihydro-5 H -cyclopenta [ c ] pyrazine-4-carboxylic acid ethyl ester

To a stirred solution of 2-hydroxy-2- (2- pendoxycyclopentyl) malonate (5 g, crude material) in acetic acid (35 mL) at room temperature, hydrazine monoamine was added. Hydrochloride (6.59 g, 96.9 mmol). The reaction mixture was heated to 100 ° C and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture with saturated NaHCO ₃ solution (100 mL) and quenched with extracted with EtOAc (2 x 60mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 3-hydroxy-6,7-dihydro-5H-cyclopenta [ c ] as an off-white solid. Pyrazine-4-carboxylic acid ethyl ester (800 mg, 3.84 mmol, 20%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 12.85 (brs, 1H), 4.26 (q, J = 7.1Hz, 2H), 2.86 (t, J = 7.4Hz, 2H), 2.72 (t, J = 7.5Hz, 2H), 2.05-1.96 (m, 2H), 1.26 (t, J = 7.1Hz, 3H)

LC-MS: m / z 208.9 [M + H] ⁺ at 1.58 RT (39.74% purity)

3-chloro-6,7-dihydro-5 H -cyclopenta [ c ] pyrazine-4-carboxylic acid ethyl ester

In a sealed tube, 3-hydroxy-6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylic acid ethyl ester (800mg, 3.85mmol) was added to 1 at room temperature under an inert atmosphere. To a stirred solution in 4,4-dioxane (8 mL) was added phosphonium chloride (3.59 mL, 38.46 mmol). The reaction mixture was heated to 100 ° C and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture with saturated NaHCO ₃ solution (30mL) and quenched extracted with EtOAc (2 x 30mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 3-chloro-6,7-dihydro- 5H -cyclopenta [ c ] as a brown solid. Ethylazine-4-carboxylic acid ethyl ester (300 mg, 1.32 mmol, 34%).

¹ H NMR (400MHz, CDCl ₃ ): δ 4.46 (q, J = 7.1Hz, 2H), 3.25 (t, J = 7.8Hz, 2H), 3.10 (t, J = 7.6Hz, 2H), 2.28-2.20 (m, 2H), 1.42 (t, J = 7.2Hz, 3H)

LC-MS: m / z 227.0 [M + H] ⁺ at 2.25 RT (93.52% purity)

6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylic acid ethyl ester

To ethyl 3-chloro-6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylate (300 mg, 1.33 mmol) in ethyl acetate (8 mL) at room temperature under an inert atmosphere. The stirred solution was added with 10% Pd / C (50% wet, 120 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 1 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with methanol (15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH ₂ Cl ₂ ) to obtain 6,7-dihydro-5 H -cyclopenta [ c ] pyrazine- as a brown slurry. Ethyl 4-formate (100 mg, 0.52 mmol, 39%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.21 (s, 1H), 4.37 (q, J = 7.0Hz, 2H), 3.27 (t, J = 7.5Hz, 2H), 3.18 (t, J = 7.8Hz, 2H), 2.13-2.07 (m, 2H), 1.35 (t, J = 7.1Hz, 3H)

LC-MS: m / z 192.9 [M + H] ⁺ at 1.83 RT (92.05% purity)

6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylic acid

Stirring 6,7-dihydro-5 H -cyclopenta [ c ] pyrazine-4-carboxylic acid ethyl ester (100 mg, 0.52 mmol) in a mixture of THF / water (4: 1,2 mL) at room temperature The solution was added lithium hydroxide monohydrate (66 mg, 1.56 mmol) and the mixture was stirred for 4 h. The reaction mixture was lyophilized to obtain 6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylic acid (120 mg, 0.73 mmol) as an off-white solid. The crude material was used in the next step without further purification.

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.22 (s, 1H), 3.28 (t, J = 7.6Hz, 2H), 3.19 (t, J = 7.8Hz, 2H), 2.14-2.06 (m, 2H)

LC-MS: m / z 165.0 [M + H] ⁺ at 2.03 RT (89.57% purity)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6,7-dihydro-5 H -cyclopenta [ c ] pyrazine-4-carboxamide

Stirring N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (111 mg, 0.61 mmol) in ethyl acetate (6 mL) under an inert atmosphere at 0 ° C. The solution was added with 6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxylic acid (100 mg, crude material), triethylamine (0.34 mL, 2.44 mmol) and propylphosphonic anhydride (50% in EtOAc (0.97 mL, 1.52 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture (20mL) was quenched with saturated NaHCO ₃ solution and extracted with EtOAc (2 x 20mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to obtain N- (2- (cyclopropylamino) -4,5-difluorobenzene as a brown solid. ) -6,7-dihydro- 5H -cyclopenta [ c ] pyrazine-4-carboxamide (100 mg, 0.3 mmol, 50%).

LC-MS: m / z 330.9 [M + H] ⁺ at 2.59 RT (38.96% purity)

4- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -6,7-dihydro-5 H -cyclopenta [ c ] pyrazine (Ex .121)

N- (2- (cyclopropylamino) -4,5-difluorophenyl) -6,7-dihydro-5 H -cyclopenta [ c ] pyrazine at room temperature under an inert atmosphere To a stirred solution of 4-formamidine (75 mg, 0.23 mmol) in ethanol (0.75 mL) was added 6 N HCl (0.75 mL) dropwise. The reaction mixture was heated to 50 ° C and stirred for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 20mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. This batch was combined with another batch (20 mg, crude material) and purified by preparative HPLC to give 4- (1-cyclopropyl-5,6-difluoro-1 H -benzo [[beta]] as an off-white solid [ d ] imidazol-2-yl) -6,7-dihydro- 5H -cyclopenta [ c ] pyrazine Ex. 121 (20 mg, 0.06 mmol, 28%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.36 (s, 1H), 7.70 (dd, J = 10.0, 7.2Hz, 1H), 7.61 (dd, J = 10.4, 7.3Hz, 1H), 3.80-3.75 (m, 1H), 3.36-3.32 (m, 2H), 3.30-3.27 (m, 2H), 2.28-2.21 (m, 2H), 1.18-1.12 (m, 2H), 0.75-0.69 (m, 2H)

LC-MS: m / z 313.0 [M + H] ⁺ at 2.47 RT (99.66% purity)

HPLC: 99.76%

[Example 122]

N- (2- (cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

To N ¹ -cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (300 mg, crude material) and 6- (difluoromethyl) pyridazine-4 at 0 ° C under an inert atmosphere. -A stirred solution of formic acid Int-29 (314mg, 1.81mmol) in ethyl acetate (10mL) was added dropwise triethylamine (0.51mL, 3.61mmol) and propylphosphonic anhydride (50% in EtOAc, 2.87mL, 4.52 mmol) and the reaction was allowed to stir at the same temperature for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0 ℃, and extracted with EtOAc (2 x 25mL) with saturated NaHCO ₃ solution (pH about 8) and basified. The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was washed with n-hexane (2 x 20 mL) and dried under vacuum to give N- (2- (cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) DA as a yellow solid Azine-4-methylamidine (320 mg, 1.0 mmol, 55%). The material was used in the next step without further purification.

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.05 (br s, 1H), 9.79 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 7.52-7.28 (m , 1H), 7.12 (dd, J = 8.4, 6.4 Hz, 1H), 6.74 (dd, J = 11.9, 2.6 Hz, 1H), 6.41 (td, J = 8.4, 2.9 Hz, 1H), 6.15 (br s , 1H), 2.37-2.31 (m, 1H), 0.76-0.70 (m, 2H), 0.44-0.40 (m, 2H)

LC-MS: m / z 322.9 [M + H] ⁺ at 2.80 RT (99.46% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole (Ex. 122)

N- (2- (cyclopropylamino) -4-fluorophenyl) -6- (difluoromethyl) pyrazine-4-carboxamide 2 (320 mg, A stirred solution of 1.0 mmol) in ethanol (4 mL) was added 6 N HCl (4 mL). Subsequently, the reaction mixture was stirred in a preheated oil bath at 70 ° C. for 30 min. After consuming the starting material (by TLC), the reaction mixture was cooled to 0 ° C; basified using a saturated NaHCO ₃ solution (pH about 8) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (difluoromethyl) pyridazine as a pale yellow solid. (4-yl) -6-fluoro- 1H -benzo [ d ] imidazole B-680 (250 mg, 0.82 mmol, 82%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.00 (d, J = 2.1Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 7.82 (dd, J = 8.9,4.9Hz, 1H) , 7.60-7.28 (m, 2H), 7.24-7.19 (m, 1H), 4.01-3.96 (m, 1H), 1.23-1.15 (m, 2H), 0.83-0.77 (m, 2H)

LC-MS: m / z 304.9 [M + H] ⁺ at 2.73 RT (99.60% purity)

HPLC: 99.62%

[Example 123]

1-Cyclopropyl-5,6-difluoro-2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.123)

To 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-thiol at 0 ° C under an inert atmosphere Ex.102 (100 mg, 0.33 mmol) in a stirred solution of acetonitrile (3 mL) was added triethylamine (0.07 mL, 0.49 mmol), followed by methyl iodide (0.02 mL, 0.39 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 24 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6- (formaldehyde) as an off-white solid. thio-yl) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.123 (50mg, 0.16mmol, 48% ).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.52 (d, J = 1.9Hz, 1H), 8.17 (d, J = 1.9Hz, 1H), 7.89-7.82 (m, 2H), 3.95-3.90 ( m, 1H), 2.72 (s, 3H), 1.21-1.14 (m, 2H), 0.80-0.74 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.75 RT (98.20% purity)

HPLC: 98.82%

[Example 124]

1-cyclopropyl-5,6-difluoro-2- (6- (isopropylthio) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 124)

To 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-thiol at room temperature under an inert atmosphere Ex.102 (100 mg, 0.33 mmol) in a stirred solution of DMF (3 mL) was added triethylamine (0.14 mL, 0.98 mmol) and 2-bromopropane (61 mg, 0.49 mmol) and the reaction was stirred for 24 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) followed by preparative HPLC to give 1-cyclopropyl-5,6-difluoro-2- as an off-white solid. (6- (isopropylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 124 (40 mg, 0.11 mmol, 35%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.52 (d, J = 2.0Hz, 1H), 8.10 (d, J = 2.0Hz, 1H), 7.89-7.81 (m, 2H), 4.23-4.16 ( m, 1H), 3.94-3.89 (m, 1H), 1.45 (d, J = 6.8Hz, 6H), 1.19-1.14 (m, 2H), 0.81-0.75 (m, 2H)

LC-MS: m / z 346.9 [M + H] ⁺ at 3.24 RT (98.03% purity)

HPLC: 99.28%

[Example 125]

1-cyclopropyl-2- (6-((difluoromethyl) thio) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex. 125)

To a 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3- in a sealed tube at room temperature under an inert atmosphere A stirred solution of thiol Ex. 102 (100 mg, 0.33 mmol) in DMF (3 mL) was added sodium 2-chloro-2,2-difluoroacetate (130 mg, 0.66 mmol) and potassium carbonate (68 mg, 0.49 mmol). The reaction mixture was heated to 80 ° C and stirred for 18 h. After consuming the starting material (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1-cyclopropyl-2- (6-((difluoromethyl) thio) as an off-white solid. ) Dazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole Ex. 125 (40 mg, 0.11 mmol, 34%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.74 (d, J = 1.8Hz, 1H), 8.43 (d, J = 1.8Hz, 1H), 8.32-8.02 (m, 1H), 7.91-7.83 ( m, 2H), 3.96-3.88 (m, 1H), 1.23-1.15 (m, 2H), 0.84-0.77 (m, 2H)

LC-MS: m / z 354.9 [M + H] ⁺ at 3.06 RT (98.26% purity)

HPLC: 99.31%

[Example 126]

6-Chloro- N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide at 6 ° C to 6-chloropyrazine- A stirred solution of 4-formic acid (200 mg, 1.08 mmol) in DMF (4 mL) was added N ¹ -cyclopropyl-4,5-difluorobenzene-1,2-diamine Int-5 (172 mg, 1.08 mmol), HATU (495 mg, 1.30 mmol) and diisopropylethylamine (0.78 mL, 4.35 mmol). The reaction mixture was stirred at room temperature for 16 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 6-chloro- N- (2- (cyclopropylamino) -4,5 as a yellow solid. -Difluorophenyl) pyridazine-4-carboxamide (100 mg, 0.30 mmol, 28%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.50 (s, 1H), 7.95 (d, J = 1.6Hz, 1H), 7.74 (brs, 1H), 7.37 (dd, J = 10.5, 8.5Hz, 1H) , 7.06 (dd, J = 12.4, 7.7Hz, 1H), 4.16-4.03 (m, 1H), 2.51-2.40 (m, 1H), 0.83-0.75 (m, 2H), 0.56-0.47 (m, 2H)

5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-ol (Ex.126)

To 0-chloro- N- (2- (cyclopropylamino) -4,5-difluorophenyl) pyrazine-4-carboxamide (500mg, 1.54mmol) at 0 ° C under an inert atmosphere. To the stirred solution in EtOH (5 mL) was added 6 N HCl (7.5 mL). The reaction mixture was stirred at 100 ° C for 3 h. After consuming the starting material (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain an off-white solid 5- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazole - 2-yl) pyridazin-3-ol Ex. 126 (300 mg, 1.04 mmol, 67%).

¹ H NMR (500MHz, CD ₃ COOD): δ 8.70 (s, 1H), 7.94 (s, 1H), 7.80 (dd, J = 10.1, 7.2Hz, 1H), 7.65 (dd, J = 9.9, 7.0Hz , 1H), 3.82-3.72 (m, 1H), 1.41-1.32 (m, 2H), 1.05-0.90 (m, 2H)

LC-MS: m / z 289.9 [M + H] ⁺ at 2.15 RT (91.69% purity)

HPLC: 91.55%

[Example 127]

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (Ex.127)

To 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-ol Ex.126 ( 1g, 3.47mmol) in a stirred solution of N -methyl-2-pyrrolidone (15mL) was added sodium hydroxide (972mg, 24.3mmol) followed by sodium 2-chloro-2,2-difluoroacetate (1.06 g, 6.94 mmol). The reaction mixture was heated to 120 ° C and stirred for 24 h. After consuming the starting material (by TLC & LCMS), the mixture was cooled and combined with a second batch (200 mg). The combined reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (difluoromethoxy) pyridazine as an off-white solid. -4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole Ex. 127 (80 mg, 0.24 mmol, 6% from two batches).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 9.69 (d, J = 1.4Hz, 1H), 8.16-8.00 (m, 2H), 7.93-7.84 (m, 2H), 3.97-3.92 (m, 1H ), 1.22-1.17 (m, 2H), 0.83-0.78 (m, 2H)

LC-MS: m / z 338.9 [M + H] ⁺ at 3.00 RT (96.39% purity)

HPLC: 96.85%

[Example 128]

1- (5- (1-Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-ol (Ex. 128)

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) under an inert atmosphere at 0 ° C. A stirred solution of aceto-1-one Ex. 64 (300 mg, 0.95 mmol) in methanol (12 mL) was added sodium borohydride (36 mg, 0.95 mmol) and the mixture was stirred at the same temperature for 1 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -Benzo [ d ] imidazol-2-yl) pyrazin- 3-yl) ethan- 1-ol Ex. 128 (150 mg, 0.47 mmol, 50%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.71 (d, J = 2.3Hz, 1H), 8.34 (d, J = 2.1Hz, 1H), 7.90-7.81 (m, 2H), 5.78 (d, J = 4.9 Hz, 1H), 5.15-5.07 (m, 1H), 3.96-3.91 (m, 1H), 1.52 (d, J = 6.5Hz, 3H), 1.24-1.16 (m, 2H), 0.79-0.73 (m, 2H)

LC-MS: m / z 317.0 [M + H] ⁺ at 2.17 RT (99.24% purity)

HPLC: 98.70%

[Example 129]

[Program]

1-cyclopropyl-5,6-difluoro-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 129)

To 1- (5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) under an inert atmosphere at 0 ° C. A stirred solution of ethyl-1-ol Ex. 128 (100 mg, 0.32 mmol) in CH ₂ Cl ₂ (3 mL) was added diethylaminosulfur trifluoride (0.06 mL, 0.47 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (20 mL), neutralized with a saturated sodium carbonate solution and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was combined with another crude material batch (25 mg) and the combined material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropane as an off-white solid -5,6-difluoro-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole Ex. 129 (40 mg, 0.12 mmol, 32%, For two batches).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.82 (d, J = 2.1Hz, 1H), 8.37 (d, J = 2.1Hz, 1H), 7.91-7.83 (m, 2H), 6.22-6.02 ( m, 1H), 4.00-3.94 (m, 1H), 1.84-1.75 (m, 3H), 1.21-1.15 (m, 2H), 0.80-0.75 (m, 2H)

LC-MS: m / z 318.9 [M + H] ⁺ at 2.69 RT (98.49% purity)

HPLC: 97.92%

[Example 130]

1-cyclopropyl-5,6-difluoro-2- (6-((trifluoromethyl) thio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex. 130)

To 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-thiol at room temperature under an inert atmosphere Ex.102 (200 mg, 0.66 mmol) in a stirred solution of acetonitrile / water (1: 1, 3 mL) was added sodium trifluoromethanesulfinate (205 mg, 1.31 mmol), potassium persulfate (355 mg, 1.31 mmol), and silver nitrate ( 11 mg, 0.06 mmol). The reaction mixture was heated to 80 ° C and stirred for 18 h. After consuming the starting material (by TLC), the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 15% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2- (6-(( trifluoromethyl) thio) pyridazine-4-yl) -1 H - benzo [d] imidazole Ex.130 (75mg, 0.2mmol, 31% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.85 (d, J = 2.0Hz, 1H), 8.34 (d, J = 1.9Hz, 1H), 7.62 (dd, J = 10.0,7.3Hz, 1H), 7.44 (dd, J = 9.5, 6.9Hz, 1H), 3.69-3.63 (m, 1H), 1.40-1.33 (m, 2H), 0.92-0.86 (m, 2H)

LC-MS: m / z 373.0 [M + H] ⁺ at 3.21 RT (98.19% purity)

HPLC: 98.55%

[Example 131 & Example 132]

N -cyclopropyl-2-nitroaniline

To 1-fluoro-2-nitrobenzene (1 g, 7.09 mmol) was added dropwise cyclopropylamine (1.47 mL, 21.28 mmol) at room temperature under an inert atmosphere and the mixture was stirred for 24 h. After consuming the starting material (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to obtain N -cyclopropyl-2-nitroaniline (720 mg, 4.04 mmol, 60%) as a yellow solid.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.15 (dd, J = 8.6, 1.4 Hz, 1H), 8.07 (brs, 1H), 7.50-7.44 (m, 1H), 7.32 (dd, J = 8.6, 1.2 Hz, 1H), 6.72-6.67 (m, 1H), 2.62-2.55 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.64 (m, 2H)

LC-MS: m / z 179.0 [M + H] ⁺ at 3.11 RT (99.64% purity)

N ¹ -cyclopropylbenzene-1,2-diamine & N ¹ -propylbenzene-1,2-diamine

To a stirred solution of N -cyclopropyl-2-nitroaniline (700 mg, 3.93 mmol) in methanol (10 mL) at room temperature, 10% Pd / C (50% wet, 300 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (ball pressure) for 5 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a celite pad and the celite bed was washed with methanol (15 mL). The filtrate was concentrated under reduced pressure to obtain a mixture of N ¹ -cyclopropylbenzene-1,2-diamine & N ¹ -propylbenzene-1,2-diamine (400 mg) as a brown viscous slurry. The mixture was used in the next step without further purification.

N - (2- (cyclopropyl) phenyl) -6- (difluoromethyl) -4-pyridazine & Amides 6- (difluoromethyl) - N - (2- (propyl Amine) phenyl) pyridazin-4-methylamidine

N ⁰ -cyclopropylbenzene-1,2-diamine & N ¹ -propylbenzene-1,2-diamine (400 mg, mixture) in ethyl acetate (10 mL) at 0 ° C under an inert atmosphere. To the stirred solution, 6- (difluoromethyl) pyrazine-4-carboxylic acid Int-29 (470 mg, 2.7 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added, followed by dropwise addition of propylphosphonic anhydride. (50% in EtOAc, 3.44 mL, 5.4 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mixture was washed with saturated NaHCO ₃ to pH of about 8 and extracted solution was basified with EtOAc (2 x 25mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 40-50% EtOAc / hexane) to give N- (2- (cyclopropylamino) phenyl) -6 as a pale yellow solid. - (difluoromethyl) -4-pyridazine-5 & Amides 6- (difluoromethyl) - N - (2- (propylamino) phenyl) pyridazine-4-6 of Amides Mixture (300 mg, 37%). The mixture was used in the next step without further purification.

LC-MS: m / z 305.0 [M + H] ⁺ at 2.63 RT (51.82% purity) & m / z 306.9 [M + H] ⁺ at 2.74 RT (41.52% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (Ex.131) & 2- (6- (difluoromethyl) ) Dazin-4-yl) -1-propyl-1 H -benzo [ d ] imidazole (Ex.132)

At room temperature, N- (2- (cyclopropylamino) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide & 6- (difluoromethyl) ) - N - (2- (propylamino) phenyl) -4-Amides mixture of (300mg, mixture) pyridazine in ethanol (10 mL) in the stirred solution was added dropwise 6 N HCl (6mL). The reaction mixture was heated to 50 ° C and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was cooled to 0 ° C., basified with saturated NaHCO ₃ solution to pH about 8 and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude material. The crude material was purified by normal phase preparative HPLC to give 1-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -1 H -benzo [ d as a light yellow solid, respectively [ d ] Imidazole ( Ex.131 ) (60mg, 0.21mmol) & 2- (6- (difluoromethyl) pyrazin-4-yl) -1-propyl- 1H -benzo [ d ] imidazole ( Ex. 132 ) (40 mg, 0.14 mmol).

[Analysis data of Ex.131]

¹ H NMR (400MHz, DMSO- d ₆ ): δ 10.03 (d, J = 2.0Hz, 1H), 8.57 (d, J = 2.0Hz, 1H), 7.82-7.74 (m, 2H), 7.45-7.28 ( m, 3H), 4.04-3.99 (m, 1H), 1.24-1.17 (m, 2H), 0.82-0.77 (m, 2H).

LC-MS: m / z 286.9 [M + H] ⁺ at 2.52 RT (98.41% purity)

HPLC: 99.92%

[Analysis data of Ex.132]

¹ H NMR (400MHz, DMSO- d ₆ ): δ 9.88 (d, J = 2.1Hz, 1H), 8.39 (d, J = 2.1Hz, 1H), 7.82-7.77 (m, 2H), 7.43-7.27 ( m, 3H), 4.44 (t, J = 7.5Hz, 2H), 1.81-1.70 (m, 2H), 0.78 (t, J = 7.4Hz, 3H)

LC-MS: m / z 288.9 [M + H] ⁺ at 2.61 RT (99.03% purity)

HPLC: 99.86%

[Example 133]

[Program]

6-chloro- N- (4-cyano-2- (cyclopropylamino) phenyl) pyrazine-4-carboxamide

To a stirred solution of 6-chloropyrazine-4-carboxylic acid (458 mg, 2.89 mmol) in ethyl acetate (30 mL) at 0 ° C, 4-amino-3- (cyclopropylamino) was added. ) Benzonitrile Int-6 (500 mg, 2.89 mmol), triethylamine (0.8 mL, 5.78 mmol) and propylphosphonic anhydride (50% in EtOAc, 4.6 mL, 7.22 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 h. After consuming the starting material (by TLC), the reaction mixture was poured into a saturated sodium bicarbonate solution (70 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (120 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 6-chloro- N- (4-cyano-2- (cyclopropylamine) as a pale yellow solid. (Yl) phenyl) pyridazine-4-carboxamide (650 mg, 2.07 mmol, 72%).

¹ H NMR (400MHz, DMSO- d ₆ ) : δ 10.17 (s, 1H), 9.63 (d, J = 1.8Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 8.0, 1.9 Hz, 1H), 6.31 (s, 1H), 2.45-2.38 (m, 1H), 0.82- 0.77 (m, 2H), 0.48-0.43 (m, 2H)

LC-MS: m / z 312.1 [MH] - in 2.57 RT (80.47% purity)

1-cyclopropyl-2- (6-hydroxypyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

At room temperature, 6-chloro- N- (4-cyano-2- (cyclopropylamino) phenyl) pyrazine-4-carboxamide (1 g, 3.19 mmol) in ethanol was added under an inert atmosphere. (15 mL) of the stirred solution was added 6 N HCl (22.5 mL). The reaction mixture was heated to 60 ° C and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was basified to a pH of about 8 using ice-cold saturated sodium bicarbonate solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 2-5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6-hydroxypyridazine-4) as a brown solid. - yl) -1 H - benzo [d] imidazole-6-carbonitrile (500mg, 1.8mmol, 56%) .

¹ H NMR (500MHz, DMSO- d ₆ ): δ 13.36 (br s, 1H), 8.41 (d, J = 2.3Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.7Hz, 1H ), 7.72-7.67 (m, 1H), 7.54 (s, 1H), 3.91-3.84 (m, 1H), 1.26-1.19 (m, 2H), 0.94-0.87 (m, 2H)

LC-MS: m / z 277.9 [M + H] ⁺ at 2.10 RT (91.16% purity)

1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.133)

To a 1-cyclopropyl-2- (6-hydroxypyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile in a sealed tube at room temperature under an inert atmosphere ( 350 mg, 1.26 mmol) in a stirred solution of DMF (3.5 mL) was added sodium 2-chloro-2,2-difluoroacetate (290 mg, 1.89 mmol) and potassium carbonate (349 mg, 2.53 mmol). The vessel was sealed and the reaction mixture was heated to 90 ° C and stirred for 32 h. The reaction mixture was cooled, quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) followed by preparative HPLC to obtain 1-cyclopropyl-2- (6- (di difluoromethoxy) pyridazine-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile Ex.133 (5mg, 0.01mmol, 1% ).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.72 (d, J = 1.8Hz, 1H), 8.03-8.01 (m, 1H), 7.98-7.77 (m, 3H), 7.64-7.61 (m, 1H), 3.73-3.68 (m, 1H), 1.45-1.38 (m, 2H), 0.95-0.89 (m, 2H)

LC-MS: m / z 328.2 [M + H] ⁺ at 2.33 RT (99.76% purity)

HPLC: 99.44%

[Example 134 & Example 135]

N- (2- (cyanomethyl) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide

To a stirred solution of 6- (difluoromethyl) pyrazine-4-carboxylic acid Int-29 (1 g, 5.75 mmol) in ethyl acetate (60 mL) was added 2- (2- Aminophenyl) acetonitrile (759 mg, 5.75 mmol) and triethylamine (1.6 mL, 11.49 mmol). To this was added propylphosphonic anhydride (50% in EtOAc, 9.14 mL, 14.37 mmol) dropwise at 0 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consuming the starting material (by TLC), the reaction mixture was basified to a pH of about 8 using a saturated sodium bicarbonate solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was triturated with n-pentane (2 x 25 mL) and dried under vacuum to give N- (2- (cyanomethyl) phenyl) -6- (difluoromethyl) pyridazine-4- as a yellow solid Formamidine (1.4 g, 4.86 mmol, 85%).

¹ H NMR (500MHz, DMSO- d ₆ ): δ 10.77 (s, 1H), 9.80 (s, 1H), 8.45 (s, 1H), 7.54-7.49 (m, 1H), 7.45-7.30 (m, 4H ), 4.02 (s, 2H)

LC-MS: m / z 288.9 [M + H] ⁺ at 2.25 RT (98.33% purity)

2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -indole-3-carbonitrile

At 0 ° C, N- (2- (cyanomethyl) phenyl) -6- (difluoromethyl) pyrazine-4-carboxamide (1 g, 3.47 mmol) in DMF ( 20 mL) of a stirred solution was added sodium hydride (60% in mineral oil, 139 mg, 3.47 mmol). The reaction mixture was heated to 120 ° C and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl) -1 as a yellow solid. H -indole-3-carbonitrile (80 mg, 0.3 mmol, 8%).

¹ H NMR (400MHz, DMSO- d ₆ ): δ 13.21 (brs, 1H), 9.96 (d, J = 2.3Hz, 1H), 8.48 (d, J = 2.3Hz, 1H), 7.80-7.74 (m, 1H), 7.68 (d, J = 8.3Hz, 1H), 7.50-7.32 (m, 3H)

LC-MS: m / z 270.9 [M + H] ⁺ at 2.71 RT (90.28% purity)

1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -indole-3-carbonitrile (Ex.134)

In a sealed tube, at room temperature, under an inert atmosphere to 2- (6- (difluoromethyl) dazin-4-yl) -1 H -indole-3-carbonitrile (100 mg, 0.37 mmol) And a stirred solution of 1,2-dichloroethane (15 mL) was added cyclopropylboronic acid (64 mg, 0.74 mmol) and sodium carbonate (78 mg, 0.74 mmol). The mixture was flushed under argon for 5 min. In a separate sealed tube, copper (II) acetate (67 mg, 0.37 mmol) and 2,2'-bipyridine (58 mg, 0.37 mmol) were dissolved in 1,2-dichloroethyl at room temperature under an inert atmosphere. In alkane (10 mL) and flushed under argon for 5 min. The vessel was sealed and the reaction mixture was heated to 80 ° C and stirred for 3 min. The resulting blue solution was added to the premixed boric acid above and the resulting mixture was rinsed under argon for 5 min. The vessel was sealed and the reaction mixture was heated to 80 ° C and stirred for 4 h. After consuming the starting material (by TLC), the reaction mixture was acidified using a 1 N HCl solution (25 mL) and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 15-20% EtOAc / hexane) to obtain 1-cyclopropyl-2- (6- (difluoromethyl)) as a pale yellow solid. Pyrazin -4-yl) -1 H -indole-3-carbonitrile Ex. 134 (11 mg, 0.03 mmol, 9%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.71 (d, J = 2.0Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.73 (d , J = 8.4Hz, 1H), 7.49 (td, J = 7.7, 1.0Hz, 1H), 7.43-7.37 (m, 1H), 7.21-6.91 (m, 1H), 3.67-3.59 (m, 1H), 1.25-1.17 (m, 2H), 0.75-0.68 (m, 2H)

LC-MS: m / z 310.9 [M + H] ⁺ at 3.08 RT (98.05% purity)

HPLC: 97.84%

2- (6- (difluoromethyl) pyridazin-4-yl) -1-methyl-1 H -indole-3-carbonitrile (Ex.135)

To 2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -indole-3-carbonitrile (35 mg, 0.13 mmol) in DMF (0.8 mL at 0 ° C under an inert atmosphere). To the stirred solution in), sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol) was added and the mixture was stirred for 5 min. Methyl iodide (0.01 mL, 0.15 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 1 h. After consuming the starting material (by TLC), the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 2- (6- (difluoromethyl) pyridazin-4-yl)-as a pale yellow solid. 1-methyl-1 H -indole-3-carbonitrile Ex. 135 (10 mg, 0.03 mmol, 28%).

¹ H NMR (400MHz, CDCl ₃ ): δ 9.57 (d, J = 2.1Hz, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.85 (dt, J = 7.9, 0.9Hz, 1H), 7.53 -7.50 (m, 2H), 7.45-7.39 (m, 1H), 7.23-6.92 (m, 1H), 3.88 (s, 3H)

LC-MS: m / z 284.9 [M + H] ⁺ at 2.81 RT (98.36% purity)

HPLC: 99.44%

[Example 136]

1-cyclopropyl-2- (6- (1-ethoxyvinyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

To 2- (6-chloropyridazin-4-yl) -1-cyclopropyl- 1H -benzo [ d ] imidazole-6-carbonitrile Ex.34 (750mg, A stirred solution of 2.54 mmol) in toluene (7.5 mL) was added tributyl (1-ethoxyvinyl) stannane (0.86 mL, 2.54 mmol) and Pd (PPh ₃ ) ₄ (294 mg, 0.25 mmol). The reaction mixture was flushed under argon for 5 min and heated to reflux temperature and stirred for 16 h. After consuming the starting material (by TLC), the reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL). The filtrate was washed with water (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50-60% EtOAc / hexane) to give 1-cyclopropyl-2- (6- (1-ethoxy) as a pale yellow solid. vinyl) pyridazin-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile (425mg, 1.28mmol, 50%) .

LC-MS: m / z 331.9 [M + H] ⁺ at 2.80 RT (56.84% purity)

2- (6-Ethylpyridazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile

To 1-cyclopropyl-2- (6- (1-ethoxyvinyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6- A stirred solution of acetonitrile (425 mg, 1.28 mmol) in acetone (2.2 mL) was added 2.5 N HCl (0.44 mL) and the mixture was stirred for 1 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (50 mL) and washed with a saturated sodium bicarbonate solution (30 mL) and water (30 mL). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was triturated with n-pentane (2 x 10 mL) to give 2- (6-ethylpyridazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole as an off-white solid. 6-carbonitrile (380 mg, 1.25 mmol, 97%).

LC-MS: m / z 304.0 [M + H] ⁺ at 2.35 RT (53.18% purity).

1-cyclopropyl-2- (6- (1-hydroxyethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile

To 2- (6-Ethylpyridazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (380mg, 1.25 mmol) in a stirred solution of methanol (4 mL) was added sodium borohydride (48 mg, 1.25 mmol) and the mixture was stirred for 1 h. After consuming the starting material (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ (2 x 25 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 4-5% MeOH / CH ₂ Cl ₂ ) to obtain 1-cyclopropyl-2- (6- (1-hydroxyethyl) as an off-white solid. yl) pyridazin-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile (300mg, 0.98mmol, 78%) .

LC-MS: m / z 305.9 [M + H] ⁺ at 1.92 RT (56.55% purity)

1-cyclopropyl-2- (6- (1-fluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (Ex.136)

To 1-cyclopropyl-2- (6- (1-hydroxyethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile at 0 ° C under an inert atmosphere (300mg, 0.98mmol) in CH of the ₂ Cl ₂ (3mL) was added a stirred solution of diethylamino sulfur trifluoride (0.19mL, 1.47mmol) and the reaction stirred for 30min. After consuming the starting material (by TLC), the reaction mixture was neutralized with a saturated sodium carbonate solution and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried ₂ SO ₄ and concentrated under reduced pressure over anhydrous Na. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to obtain the desired compound (35 mg). This material was combined with another batch (10 mg) and purified by preparative HPLC to give 1-cyclopropyl-2- (6- (1-fluoroethyl) pyridazin-4-yl)-as an off-white solid 1 H -benzo [ d ] imidazole-6-carbonitrile Ex. 136 (21 mg, 0.07 mmol, 6% for two batches).

¹ H NMR (400MHz, CD ₃ OD): δ 9.83 (d, J = 2.0Hz, 1H), 8.50 (d, J = 2.1Hz, 1H), 8.28-8.26 (m, 1H), 7.93 (dd, J = 8.4, 0.6Hz, 1H), 7.70 (dd, J = 8.4, 1.5Hz, 1H), 6.19-6.01 (m, 1H), 3.99-3.94 (m, 1H), 1.93-1.81 (m, 3H) 1.37-1.28 (m, 2H), 0.93-0.86 (m, 2H)

LC-MS: m / z 308.0 [M + H] ⁺ at 2.55 RT (99.50% purity)

HPLC: 99.43%

Example 137: Metalloenzyme activity

A. Preparation of V79-4 cells expressing recombinant adrenocortical ferredoxin and adrenocortical ferredoxin reductase and recombinant human CYP11B2 or CYP11B1 according to the method described previously (LaSala et al. 2009 Anal Bioch 394: 56-61) . From cell lysates enriched preparation of the enzyme and microsomal fraction which was then used as a source of enzyme inhibitors for determining the IC _50. The substrate Km values for 11-deoxycorticosterone (CYP11B2 substrate) and 11-deoxycortisol (CYP11B1 substrate) were determined experimentally. Enzyme assays for inhibitor screening use CYP11B2 and CYP11B1 enzyme-enriched microsomes and operate with the Km of the corresponding substrate. The product of the enzyme reaction was measured by LC-MS, namely aldosterone of CYP11B2 or cortisol of CYP11B1. Operate the test with less than 20% substrate turnover. It is determined by the product formed in the absence or presence of various concentrations of inhibitors in the generated inhibitor IC _50. In the absence of test compounds, the product formed ( _Pt ) was defined as 0% activity in each data set. In the absence of the enzyme, the product (P _b) is formed in each data set is defined as 0% activity based. The percentage of activity in the presence of each inhibitor is calculated according to the following equation:% activity = (PP _b ) / (P _t -P _b ), where P = product formed in the presence of the inhibitor. IC ₅₀ value is defined as the line with respect to a control reaction without inhibitor concentration of inhibitor causing 50% reduction of activity.

^f See Table 1 for HPLC and LCMS methods

^g IC ₅₀ range: +>10μM; ++ 1-10μM; +++ 0.1-1μM; ++++ 0.001-0.1μM

The results in Table 2 demonstrate that compounds of formula I have effective activity against CYP11B2 and that many compounds of formula I have significant selectivity for inhibiting CYP11B2 over CYP11B1.

Comparative examples were also prepared. Tables 3 and 4 show the substitution of pyridazine of compounds of Formula I with pyridine (eg, Examples 137-140), which show an inhibition (7-54 fold increase) of CYP11B1 for each comparison. These structural changes also produce compounds that are less selective for CYP11B2 than CYP11B1. Both of these characteristics are undesirable in CYP11B2 inhibitors because, as described above, CYP11B1 activity is integrated with the cortisol production system. In addition, Examples 14 and 42 demonstrated a reduction in CYP1A2 and CYP19 inhibition compared to their corresponding comparative examples. Examples 42 and 19 also show much greater metabolic stability when exposed to stone crab macaques and rat liver microsomes than their pyridine counterparts Example 139 and Example 140. Similarly, Table 5 shows that known inhibitors of CYP11B2, such as Examples 141-143, also have undesired activity against CYP11B1, thereby limiting their effectiveness as therapeutic agents. However, similar Examples 31 and 52 are much less effective inhibitors of CYP11B1. Examples 31 and 52 also possessed greater metabolic stability than Example 141. In summary, these results demonstrate that the pyrazine compound of formula I may have greater therapeutic utility in humans than known compounds, which is partly due to its reduced inhibition of CYP11B1 compared to other related metalloenzymes on CYP11B2 Its inhibition increases selectivity and its metabolic stability.

^a Calculated pKa (pKa of N2 pyrazine atom or pyridine N), LogP (Chemaxon method), and total polar surface area (tPSA) calculated with MarvinSketch 15.5.4.0

^b Selectivity = CYP11B1 IC ₅₀ / CYP11B2 IC ₅₀

^c Percent of compounds remaining in rat or stone crab macaque liver microsomes at 65 min

^d ACS Med. Chem. Lett. 2015 , 6 , 573.

^e WO 2012/012478

^a Calculated pKa (pKa of N2 pyrazine atom or pyridine N), LogP (Chemaxon method), and total polar surface area (tPSA) calculated with MarvinSketch 15.5.4.0

^b Selectivity = CYP11B1 IC ₅₀ / CYP11B2 IC ₅₀

^c Percent of compounds remaining in rat or stone crab macaque liver microsomes at 65 min

Table 5. Comparison results

^a pKa calculated with MarvinSketch 15.5.4.0 (pKa of N2 pyrazine atom or pyridine N)

^b Selectivity = CYP11B1 IC ₅₀ / CYP11B2 IC ₅₀

^c Percent of compounds remaining in rat or stone crab macaque liver microsomes at 65 min

^d J. Med. Chem. 2015 , 58 , 9382.

^e ACS Med. Chem. Lett. 2013 , 4 , 1203.

[Content incorporated by reference]

The contents of all references (including literature references, issued patents, published patent applications, and patent applications in the same application) cited throughout this application are hereby expressly incorporated by reference in their entirety.

[Equivalent]

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These equivalents are intended to be covered by the scope of the accompanying patent application.

Claims (75)

A compound of formula I or a pharmaceutically acceptable salt thereof: In the formula, A is N or CR ⁵ ; W is N or CR ⁶ ; X is N or CR ⁶ ; Y is N or CR ⁶ ; Z is N or CR ⁶ ; provided that W, X, Y, and Z are not More than two are N; R ¹ is hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , S (O) R ^d , S (O) ₂ R ^d , CH ₂ OR ^f , or CR ^e R ^f OH, of which any R ¹ may be subjected to 1 to 3 as required R ^{7 is} independently substituted; R ² is hydrogen, halogen, cyano, alkyl, or haloalkyl; or R ¹ and R ² together with the atoms attached thereto form an aryl, heterocycloalkyl, or Cycloalkyl ring; R ³ is hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aromatic Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , CO ₂ R ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH; R ⁴ is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; R ⁵ is hydrogen, alkyl, haloalkyl, Heteroalkyl, or cycloalkyl; each occurrence of R ⁶ is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, or carboxy; R ⁷ Each occurrence is independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, aryl, aryl substituted with 1 to 3 independent halogens,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h ; each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each occurrence ^{R a, R b, R c} , R d, R e, R ^f, and the system is independently hydrogen, acyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl Base, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkyl, when attached to a nitrogen atom A nitrogen protecting group when present, or an oxygen protecting group when attached to an oxygen atom; or R ^a and R ^b together with the atom attached thereto form a heterocycloalkyl ring; or R ^e and R ^f together with attached to it Atomic together Cycloalkyl ring; and ^{R g, R h, R i} , R ^j, and based on each occurrence of is independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl Alkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkyl, or R ^g and ^Rh together with the atoms attached thereto Together form a heterocycloalkyl ring. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy , Cycloalkyl, cycloalkoxy, aryl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CH ₂ NHSO ₂ R ^d , COR ^f , or CR ^e R ^f OH; or R ¹ And R ² together with the atoms attached thereto form an aryl ring. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, Aryl, NR ^a R ^b , CH ₂ NHSO ₂ R ^d , or CR ^e R ^f OH; or R ¹ and R ² together with the atoms attached thereto form an aryl ring. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: R ¹ is hydrogen, halogen, alkyl, haloalkyl, CH ₂ NHSO ₂ R ^d , or NR ^a R ^b ; and R ^a , R ^b , and ^Rd are independently hydrogen, alkyl, or haloalkyl. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a haloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ² is hydrogen or an alkyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is hydrogen and R ² is an alkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁴ is an alkyl group or a cycloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁴ is a C _1-4 alkyl group or a C _3-5 cycloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R ⁶ is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl . The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R ⁶ is independently hydrogen, halogen, or cyano. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein A is CR ⁵ and R ⁵ is hydrogen, C _1-4 alkyl, or C _3-5 cycloalkyl .     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein A is N.         The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein no more than one of W, X, Y, and Z is N.     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein W, X, Y, and Z are each independently CR ⁶ .     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein Z is N.     The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has formula Ia :     The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein A is N.     The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has the formula Ib : The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has the formula Ic : The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has the formula Id : The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has formula Ie : The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has the formula If : The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R ¹ is a haloalkyl group. The compound or pharmaceutically acceptable salt thereof according to claim 24, wherein each R ⁶ is independently halogen. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aforementioned compound has the formula Ig : The compound or a pharmaceutically acceptable salt thereof as described in claim 1, which is selected from the group consisting of 1-cyclopropyl-6-fluoro-2- (dazin-4-yl)- 1 H -benzo [ d ] imidazole (1); 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carbonitrile (2) ; 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole (3); 1-cyclopropyl-6-fluoro-2- (6-Vinylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (4); 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole-2 -Yl) pyrazine-3-carboxylic acid methyl ester (5); 1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole ( 6); 1- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl 1-ol (7); N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane Hydrazine (8); ((5- (1-cyclopropyl-6-fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) carbamate ethyl ester ( 9); 4- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) morpholine (10); 1-cyclopropane Yl-6-fluoro-2- (6- (4- (4-fluorophenyl) piperazin-1-yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (11); 2 -(5- (1-ring -6-fluoro -1 H - benzo [d] imidazol-2-yl) pyridazin-3-yl) propan-2-ol (12); 5- (1-cyclopropyl-6-fluoro-1 H - benzo [d] imidazol-2-yl) - N - (tetrahydro -2H- pyran-4-yl) pyridazin-3-amine (13); 4- (1-cyclopropyl-6 Fluoro-1 H -benzo [ d ] imidazol-2-yl) phosphonium (14); 1-cyclopropyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H- Benzo [ d ] imidazole (15); N- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethanesulfonyl Amine (16); 2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (17); 2- (4- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazin-1-yl) -N-isopropylacetamidamine (18 ); 1-cyclopropyl-5,6-difluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (19); 2- (4- (5 -(1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl ) Ethan-1-one (20); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N-methylpyrazine-3- Amine (21); 2- (6-chloropyridazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (22); 1-cyclopropyl 5,6-difluoro-2- (6-methoxy-pyridazine-4-yl) -1 H - benzo [d] imidazole (23) 1-cyclopropyl-5,6-difluoro-2- (6-isopropoxy-pyridazine-4-yl) -1 H - benzo [d] imidazole (24); 5- (1-cyclopropylmethyl -5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) -N, N-dimethylpyrazine-3-amine (25); 1-ethyl-6-fluoro- 2- (6-methylpyrazin-4-yl) -1 H -indole (26); 1-cyclopropyl-5,6-difluoro-2- (6- (2,2,2-tri Fluoroethoxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (27); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) - N - (2- methoxyethyl) pyridazin-3-amine (28); 1-cyclopropyl-2- (6-methoxy-pyridazine-4-yl) - 1 H -benzo [ d ] imidazole-6-carbonitrile (29); 1-cyclopropyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (30 ); N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) ethanesulfonamide (31) ; 5- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) - N - (2,2,2- trifluoroethyl) pyridazin -3 -Amine (32); 1-cyclopropyl-2- (6-ethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (33); 2- ( 6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-carbonitrile (34); 1-cyclopropyl-2- (6-methylpyrazine -4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (35); 1-cyclopropyl-5,6-di Fluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (36); 1- (4- (5- (1 -Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazin-1-yl) ethan-1-one (37); 1 -Cyclopropyl-5,6-difluoro-2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] Imidazole (38); 4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) piperazine-1- Tert-butyl formate (39); 1-ethyl-2- (6-methoxypyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (40); 1- Ethyl-2- (6-ethylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (41); 1-cyclopropyl-2- (6- (difluoro) (Methyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (42); 2- (6-cyclobutoxypyridazin-4-yl) -1- Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (43); 1-cyclopropyl-2- (6- (4,4-difluoropiperidin-1-yl) Azin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (44); 5-chloro-3-cyclopropyl-2- (6-methylpyridazin-4-yl ) -3 H -imidazo [4,5- b ] pyridine (45); 1-cyclopropyl-2- (6- (3,3-difluoropyrrolidin-1-yl) pyridazin-4-yl ) -5,6-difluoro -1 H - benzo [d] imidazole (46); 1- (5- (1-cyclopropyl-5,6- -1 H - benzo [d] imidazol-2-yl) pyridazin-3-yl) -2,2,2-trifluoro-l-ol (47); 1- (5- (l-cyclopropylmethyl -5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -N, N-dimethylpyrrolidin-3-amine (48); 1- Cyclopropyl-5,6-difluoro-2- (6- (4-fluorophenyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (49); 1-cyclopropyl- 5,6-difluoro-2- (6-((4-fluorophenyl) ethynyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (50); 1-cyclopropyl- 5,6-difluoro-2- (6-isopropylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (51); N -((5- (1-cyclopropyl-5 , 6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) ethanesulfonamide (52); 1-cyclopropyl-5,6-difluoro -2- (6-((1,1,1-trifluoroprop-2-yl) oxy) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (53); 3-cyclopropane 2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (54); 1-cyclopropyl-5,6-di Fluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (55); 1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl)- 4- (trifluoromethyl) -1 H -benzo [ d ] imidazole (56); 1-cyclopropyl-2- (6- (2,2-difluoropropoxy) pyridazin-4-yl ) -5,6-difluoro -1 H - benzo [d] imidazole (57); 1-cyclopropyl-5,6-difluoro-2- (5- Pyridazin-4-yl-propyl) -1 H - benzo [d] imidazole (58); 1-cyclopropyl-2- (6-cyclopropyl-pyridazin-4-yl) -5,6- Fluoro-1 H -benzo [ d ] imidazole (59); 2- (6-chloropyrazin-4-yl) -3-cyclopropyl-5-methoxy-3 H -imidazo [4,5 -b ] pyridine (60); 1-cyclopropyl-5,6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyrazin-4-yl) -1 H -benzene Benzo [ d ] imidazole (61); 1-cyclopropyl-2- (6- (2,4-difluorophenyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (62); 1-cyclopropyl-2- (6- (3,4-difluorophenyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (63); 1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) ethyl-1 -Keto (64); 2- (6-chloropyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (65); 1-cyclopropyl -2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (66); 2- (6- (difluoromethyl) Azin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (67); 2- (6-chloropyrazin-4-yl) -1-ethyl -1 H -benzo [ d ] imidazole-6-carbonitrile (68); 2- (6- (difluoromethyl) dazin-4-yl) -1-ethyl-1 H -benzo [ d ] Imidazole-6-carbonitrile (69); 1-cyclopropyl-2- (6- (1,1-difluoroethyl) pyridazine-4 -Yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (70); 1-cyclopropyl-5,6-difluoro-2- (6- (2,2,2-tri Fluoroethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (71); 2- (6-cyclopropylpyridazin-4-yl) -1-ethyl-5,6- Difluoro-1 H -benzo [ d ] imidazole (72); 5-chloro-3-cyclopropyl-2- (6- (difluoromethyl) dazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (73); 1-cyclopropyl-5,6-difluoro-2- (5-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole ( 74); 1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (75); 3-cyclopropyl-2 -(6- (difluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (76); N -((5- (1-cyclo Propyl-5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) methanesulfonamide (77); N -((5- (1 -Cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) -N -methylmethanesulfonamide (78); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propane-2-sulfonamide (79); 1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfonyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (80); 1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl)- 5,6-difluoro-1 H -benzo [ d ] imidazole (81); 1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfinamidino) pyridazine-4 -Yl) -1 H -benzo [ d ] imidazole (82); 1-cyclopropyl-2- (6- (ethylsulfinamido) pyridazin-4-yl) -5,6-difluoro -1 H -benzo [ d ] imidazole (83); 5-chloro-3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (84); 1-cyclopropyl-5,6-difluoro-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (85 ); 1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (86); 3-cyclopropyl -2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (87); 2-((5- (1-cyclopropyl -5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) isotetrahydrothiazole 1,1-dioxide (88); 3- Cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-carbonitrile (89); 1-cyclopropyl -2- (6-methylpyrazin-4-yl) -6- (trifluoromethyl) -1 H -benzo [ d ] imidazole (90); and a pharmaceutically acceptable salt thereof. A compound of formula I or a pharmaceutically acceptable salt thereof: In the formula, A is N or CR ⁵ ; W is N or CR ⁶ ; X is N or CR ⁶ ; Y is N or CR ⁶ ; Z is N or CR ⁶ ; provided that W, X, Y, and Z are not More than two are N; R ¹ is hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , OR ^f , SR ^f , CO ₂ R ^e , COR ^f , S (O) R ^d , S (O) ₂ R ^d , CH ₂ OR ^f , or CR ^e R ^f OH, where any R ¹ may optionally be substituted with 1 to 3 independent substituents R ⁷ ; R ² is hydrogen, halogen, cyano, alkyl, or haloalkyl; or R ¹ and R ² together with the atoms attached thereto form an aromatic group Group, heterocycloalkyl, or cycloalkyl ring; R ³ is hydrogen, halogen, cyano, fluorenyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, or cycloalkane Group, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , C H ₂ NHSO ₂ R ^d , CO ₂ Re ^e , COR ^f , CH ₂ OR ^f , or CR ^e R ^f OH; R ⁴ is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; R ⁵ is hydrogen , Cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; each occurrence of R ⁶ is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy Group, haloalkyl, OR ^f , or carboxyl; each occurrence of R ⁷ is independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, and 1 to 3 independent Halogen-substituted aryl,-(CH ₂ ) nC (O) NR ^g R ^h , -S (O) ₂ R ⁱ , -CO ₂ R ^j , or NR ^g R ^h ; each n is independently 1 , 8, 9, or 10; each occurrence of ^{R a, R b, R c} , R d, R e, and R ^f is independently hydrogen-based, acyl , Alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl , C (O) C _1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R ^a and R ^b together with the atom attached thereto Heterocycloalkyl ring Or R ^e and R ^f together with the atom attached thereto form a cycloalkyl ring; and each occurrence ^{R g, R h, R i} , R ^j, and the line is independently hydrogen, acyl, alkyl, alkenyl, Alkyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C (O) OC _1-6 alkyl, C (O) C _1-6 alkyl , Or R ^g and R ^h together with the atoms attached thereto form a heterocycloalkyl ring. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R ¹ is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy , Cycloalkyl, cycloalkoxy, aryl, NR ^a R ^b , NHSO ₂ R ^c , CH ₂ NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , SR ^f , COR ^f , or CR ^e R ^f OH; or R ¹ and R ² together with the atoms attached thereto form an aryl or cycloalkyl ring. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R ¹ is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, Aryl, NR ^a R ^b , CR ^e R ^f NHSO ₂ R ^d , SR ^f , or CR ^e R ^f OH; or R ¹ and R ² together with the atoms attached thereto form an aryl or cycloalkyl ring. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R ¹ is hydrogen, halogen, alkyl, haloalkyl, CR ^e R ^f NHSO ₂ R ^d , SR ^f , or NR ^a R ^B; and ^{R a, R b, R d} , R e, and R ^f is independently-based hydrogen, alkyl, or haloalkyl. The compound or a pharmaceutically acceptable salt thereof according to claim 28, wherein R ¹ is a haloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein R ² is hydrogen or an alkyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 28, wherein R ¹ is hydrogen and R ² is an alkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 34, wherein R ⁴ is an alkyl group or a cycloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 34, wherein R ⁴ is a C _1-4 alkyl group or a C _3-5 cycloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 36, wherein each R ⁶ is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl . The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 36, wherein each R ⁶ is independently hydrogen, halogen, or cyano. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 38, wherein A is CR ⁵ and R ⁵ is hydrogen, C _1-4 alkyl, or C _3-5 cycloalkyl .     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 38, wherein A is N.         The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 40, wherein no more than one of W, X, Y, and Z is N.     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 41, wherein W, X, Y, and Z are each independently CR ⁶ .     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 41, wherein Z is N.     The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Ia :     The compound or a pharmaceutically acceptable salt thereof according to claim 44, wherein A is N.     The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Ib : The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Ic : The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Id : The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Ie : The compound or a pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula If : The compound or a pharmaceutically acceptable salt thereof according to claim 50, wherein R ¹ is a haloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 50, wherein R ⁶ is independently halogen. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein the aforementioned compound has the formula Ig : A compound selected from the group consisting of: 1-cyclopropyl-6-fluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (1); 5- ( 1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carbonitrile (2); 2- (6-chloropyridazin-4-yl) -1 -Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole (3); 1-cyclopropyl-6-fluoro-2- (6-vinylpyrazin-4-yl) -1 H- Benzo [ d ] imidazole (4); 5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (5); 1 -Cyclopropyl-2- (6-ethylpyrazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole (6); 1- (5- (1-cyclopropyl-6 -Fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) -2,2,2-trifluoroethyl-1-ol (7); N -((5- (1 -Cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) propanamide (8); ((5- (1-cyclopropyl -6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) methyl) urethane (9); 4- (5- (1-cyclopropyl-6) -Fluoro- 1H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) morpholine (10); 1-cyclopropyl-6-fluoro-2- (6- (4- (4 -Fluorophenyl) piperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (11); 2- (5- (1-cyclopropyl-6-fluoro-1) H - benzo [d] imidazol-2-yl) pyridazin-3-yl) 2-ol (12); 5- (1-cyclopropyl-6-fluoro -1 H - benzo [d] imidazol-2-yl) - N - (tetrahydro-pyran-4-yl -2H- ) Dazin-3-amine (13); 4- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyridinium (14); 1-cyclopropyl- 6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (15); N- (5- (1-cyclopropyl-6-fluoro-1 H -Benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethanesulfonamide (16); 2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzene and [d] imidazole-6-carbonitrile (17); 2- (4- (5- (1-cyclopropyl-6-fluoro -1 H - benzo [d] imidazol-2-yl) pyridazin - 3-yl) piperazin-1-yl) -N-isopropylacetamidamine (18); 1-cyclopropyl-5,6-difluoro-2- (6-methylpyrazin-4-yl ) -1 H -benzo [ d ] imidazole (19); 2- (4- (5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazine -3-yl) piperazin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (20); 5- (1-cyclopropyl-5,6-difluoro-1 H -Benzo [ d ] imidazol-2-yl) -N-methylpyrazine-3-amine (21); 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-5,6 -Difluoro-1 H -benzo [ d ] imidazole (22); 1-cyclopropyl-5,6-difluoro-2- (6-methoxydazin-4-yl) -1 H -benzene Benzo [ d ] imidazole (23); 1-cyclopropyl-5,6-difluoro-2- (6-isopropoxypyrazin-4-yl)- 1 H -benzo [ d ] imidazole (24); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) -N, N-dimethyl Pyridazine-3-amine (25); 1-ethyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (26); 1-cyclopropyl- 5,6-difluoro-2- (6- (2,2,2-trifluoroethoxy) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (27); 5- (1 --cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) - N - (2- methoxyethyl) pyridazin-3-amine (28); 1- Cyclopropyl-2- (6-methoxypyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (29); 1-cyclopropyl-6-fluoro-2- (6-methylpyrazin-4-yl) -1 H -indole (30); N -((5- (1-cyclopropyl-6-fluoro-1 H -benzo [ d ] imidazole-2 -Yl) pyridazin-3-yl) methyl) ethanesulfonamide (31); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl ) - N - (2,2,2- trifluoroethyl) pyridazin-3-amine (32); 1-cyclopropyl-2- (6-ethyl-pyridazine-4-yl) -5,6 -Difluoro-1 H -benzo [ d ] imidazole (33); 2- (6-chloropyrazin-4-yl) -1-cyclopropyl-1 H -benzo [ d ] imidazole-6-form Nitrile (34); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (35); 1-cyclopropyl- 5,6-difluoro-2- (6- (4-methylpiperazin-1-yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (36); 1- (4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl ) Piperazin-1-yl) ethan-1-one (37); 1-cyclopropyl-5,6-difluoro-2- (6- (4- (methylsulfonyl) piperazine-1- Yl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (38); 4- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] Imidazol-2-yl) pyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (39); 1-ethyl-2- (6-methoxypyridazin-4-yl) -1 H -Benzo [ d ] imidazole-6-carbonitrile (40); 1-ethyl-2- (6-ethylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (41); 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (42); 2 -(6-cyclobutoxytrazin-4-yl) -1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazole (43); 1-cyclopropyl-2- (6- (4,4-difluoropiperidin-1-yl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (44); 5-chloro-3 -Cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (45); 1-cyclopropyl-2- (6- (3 , 3-difluoropyrrolidin-1-yl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (46); 1- (5- (1-cyclopropane) -5,6-difluoro -1 H - benzo [d] imidazol-2-yl) pyridazin-3-yl) 2,2,2- Ethan-l-ol (47); 1- (5- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) pyridazin-3-yl) - N, N-dimethylpyrrolidin-3-amine (48); 1-cyclopropyl-5,6-difluoro-2- (6- (4-fluorophenyl) pyridazin-4-yl)- 1 H -benzo [ d ] imidazole (49); 1-cyclopropyl-5,6-difluoro-2- (6-((4-fluorophenyl) ethynyl) pyridazin-4-yl)- 1 H -benzo [ d ] imidazole (50); 1-cyclopropyl-5,6-difluoro-2- (6-isopropylpyrazin-4-yl) -1 H -benzo [ d ] Imidazole (51); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl) methyl) ethyl Sulfonamide (52); 1-cyclopropyl-5,6-difluoro-2- (6-((1,1,1-trifluoroprop-2-yl) oxy) pyridazin-4-yl ) -1 H -benzo [ d ] imidazol (53); 3-cyclopropyl-2- (6-methylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine- 5-carbonitrile (54); 1-cyclopropyl-5,6-difluoro-2- (dazin-4-yl) -1 H -benzo [ d ] imidazole (55); 1-cyclopropyl -5,6-difluoro-2- (dazin-4-yl) -4- (trifluoromethyl) -1 H -benzo [ d ] imidazole (56); 1-cyclopropyl-2- ( 6- (2,2-difluoropropoxy) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (57); 1-cyclopropyl-5,6 - difluoro-2- (5-isopropyl-pyridazin-4-yl) -1 H - benzo [d] imidazole (58); 1- Propyl-2- (6-cyclopropyl-pyridazin-4-yl) -5,6-difluoro -1 H - benzo [d] imidazole (59); 2- (6-chloro-4-despair Yl) -3-cyclopropyl-5-methoxy- 3H -imidazo [4,5- b ] pyridine (60); 1-cyclopropyl-5,6-difluoro-2- (6- (4-fluoro-2-methylphenyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (61); 1-cyclopropyl-2- (6- (2,4-di Fluorophenyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (62); 1-cyclopropyl-2- (6- (3,4-difluoro Phenyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (63); 1- (5- (1-cyclopropyl-5,6-difluoro- 1 H -benzo [ d ] imidazol-2-yl) pyrazin-3-yl) ethan-1-one (64); 2- (6-chloropyrazin-4-yl) -1-ethyl-5 , 6-difluoro-1 H -benzo [ d ] imidazole (65); 1-cyclopropyl-2- (6- (difluoromethyl) dazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (66); 2- (6- (difluoromethyl) pyrazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] Imidazole (67); 2- (6-chloropyrazin-4-yl) -1-ethyl-1 H -benzo [ d ] imidazole-6-carbonitrile (68); 2- (6- (di Fluoromethyl) pyridazin-4-yl) -1-ethyl- 1H -benzo [ d ] imidazole-6-carbonitrile (69); 1-cyclopropyl-2- (6- (1,1 - difluoroethyl) pyridazine-4-yl) -5,6-difluoro -1 H - benzo [d] imidazole (70); 1- cyclopropylmethyl 5,6-difluoro-2- (6- (2,2,2-trifluoroethyl) pyridazine-4-yl) -1 H - benzo [d] imidazole (71); 2- (6 -Cyclopropylpyridazin-4-yl) -1-ethyl-5,6-difluoro-1 H -benzo [ d ] imidazole (72); 5-chloro-3-cyclopropyl-2- ( 6- (difluoromethyl) pyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (73); 1-cyclopropyl-5,6-difluoro-2- (5 -Methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (74); 1-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -1 H -benzene Benzo [ d ] imidazole-6-carbonitrile (75); 3-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -3 H -imidazo [4,5- b ] Pyridine-5-carbonitrile (76); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3- (Methyl) methyl) methanesulfonamide (77); N -((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazine- 3-yl) methyl) -N -methylmethanesulfonamide (78); N -((5- (1-cyclopropyl-5,6-difluoro- 1H -benzo [ d ] imidazole- 2-yl) pyridazin-3-yl) methyl) propane-2-sulfonamide (79); 1-cyclopropyl-5,6-difluoro-2- (6- (methylsulfonyl) (Pyrazin-4-yl) -1 H -benzo [ d ] imidazole (80); 1-cyclopropyl-2- (6- (ethylsulfonyl) pyridazin-4-yl) -5,6 -Difluoro-1 H -benzo [ d ] imidazole (81); 1-cyclopropyl-5,6 -Difluoro-2- (6- (methylsulfinamilide) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (82); 1-cyclopropyl-2- (6- ( Ethylsulfinyl) pyridazin-4-yl) -5,6-difluoro- 1H -benzo [ d ] imidazole (83); 5-chloro-3-cyclopropyl-2- (6- Cyclopropylpyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (84); 1-cyclopropyl-5,6-difluoro-2- (6- (trifluoromethyl) Yl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (85); 1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -Benzo [ d ] imidazole-6-carbonitrile (86); 3-cyclopropyl-2- (6-cyclopropylpyridazin-4-yl) -3 H -imidazo [4,5- b ] Pyridine-5-carbonitrile (87); 2-((5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3-yl ) Methyl) isotetrahydrothiazole 1,1-dioxide (88); 3-cyclopropyl-2- (6- (trifluoromethyl) dazin-4-yl) -3 H -imidazo [ 4,5- b ] pyridine-5-carbonitrile (89); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -6- (trifluoromethyl) -1 H -benzene Benzo [ d ] imidazole (90); N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyridazin-3- (Yl) ethyl) methanesulfonamide (91); 1-cyclopropyl-5,6-difluoro-2- (6- (fluoromethyl) pyrazin-4-yl) -1 H -benzo [ d] imidazole (92); 1-cyclopropyl-2- (5,6- Pyridazin-4-yl) -5,6-difluoro -1 H - benzo [d] imidazole (93); (5- (1-cyclopropyl-5,6-difluoro -1 H - benzene And [[ d ] imidazol-2-yl) pyridazin-3-yl) methanol (94); 5-chloro-3-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -3 H -imidazo [4,5- b ] pyridine (95); N- (1- (5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [d] imidazole- 2-yl) pyridazin-3-yl) ethyl) ethanesulfonamide (96); 2- (6-butylpyrazin-4-yl) -1-cyclopropyl-5,6-difluoro- 1 H -benzo [ d ] imidazole (97); 1-cyclopropyl-6-methyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (98 ); 1-cyclopropyl-5,6-difluoro-2- (3-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (99); 1-cyclopropyl-2 -(3,6-dimethylpyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (100); 1-cyclopropyl-2- (6- (di Fluoromethyl) pyridazin-4-yl) -6,7-difluoro-1 H -benzo [ d ] imidazole (101); 5- (1-cyclopropyl-5,6-difluoro-1 H -Benzo [ d ] imidazol-2-yl) pyrazine-3-thiol (102); 2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (103); 2- (6- (difluoromethyl) pyridazin-4-yl) -5,6-difluoro-1-methyl-1 H -benzo [ d ] Imidazole (104); 2- (6- (difluoromethyl) pyridazin-4-yl) -5,6- Fluoro-1-propyl -1 H - benzo [d] imidazole (105); 4- (1-cyclopropyl-5,6-difluoro -1 H - benzo [d] imidazol-2-yl) -5,6,7,8-tetrahydropyridoline (106); 1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole-5- Nitrile (107); 1-cyclobutyl-5,6-difluoro-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (108); 1-ring Propyl-2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-ol (109); 5- (1-cyclopropyl-5, 6-difluoro-1 H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid (110); 1-cyclopropyl-7-fluoro-2- (6-methylpyrazine-4 -Yl) -1 H -benzo [ d ] imidazole (111); 5-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] Imidazole (112); 4-chloro-1-cyclopropyl-2- (6-methylpyrazin-4-yl) -1 H -benzo [ d ] imidazole (113); 1-cyclopropyl-5 , 6-difluoro-2- (6- (methoxymethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (114); 5- (6-cyano-1-ring Propyl- 1H -benzo [ d ] imidazol-2-yl) pyrazine-3-carboxylic acid methyl ester (115); 5- (6-cyano-1-cyclopropyl- 1H -benzo [ d] ] Imidazol-2-yl) pyridazin-3-carboxylic acid (116); 1-cyclopropyl-2- (6- (cyclopropylmethoxy) pyridazin-4-yl) -5,6-difluoro -1 H - benzo [d] imidazole (117) 1-cyclopropyl-2- (6- (2,2,2-trifluoroethoxy) pyridazine-4-yl) -1 H - benzo [d] imidazole-6-carbonitrile (118); 6-chloro-1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro-1 H -benzo [ d ] imidazole (119); 1-cyclopropane 2- (6- (difluoromethyl) pyridazin-4-yl) -5-fluoro- 1H -benzo [ d ] imidazole-6-carbonitrile (120); 4- (1-cyclopropane -5,6-difluoro- 1H -benzo [ d ] imidazol-2-yl) -6,7-dihydro- 5H -cyclopenta [ c ] pyrazine (121); 1-cyclopropyl -2- (6- (difluoromethyl) pyridazin-4-yl) -6-fluoro-1 H -benzo [ d ] imidazole (122); 1-cyclopropyl-5,6-difluoro- 2- (6- (methylthio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (123); 1-cyclopropyl-5,6-difluoro-2- (6- (Isopropylthio) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (124); 1-cyclopropyl-2- (6-((difluoromethyl) thio)) Azin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (125); 5- (1-cyclopropyl-5,6-difluoro-1 H -benzo [ d ] Imidazol-2-yl) pyridazin-3-ol (126); 1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -5,6-difluoro- 1 H -benzo [ d ] imidazole (127); 1- (5- (1-cyclopropyl-5,6-difluoro-1) 1 -H -benzo [ d ] imidazol-2-yl) pyrazine-3 -Yl) ethane-1-ol (128); 1-cyclopropyl-5,6-difluoro-2- (6- ( 1-fluoroethyl) pyrazin-4-yl) -1 H -benzo [ d ] imidazole (129); 1-cyclopropyl-5,6-difluoro-2- (6-((trifluoromethyl) Yl) thio) pyridazin-4-yl) -1 H -benzo [ d ] imidazole (130) 1-cyclopropyl-2- (6- (difluoromethyl) pyridazin-4-yl)- 1 H -benzo [ d ] imidazole (131); 2- (6- (difluoromethyl) pyridazin-4-yl) -1-propyl-1 H -benzo [ d ] imidazole (132); 1-cyclopropyl-2- (6- (difluoromethoxy) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (133); 1-cyclopropyl- 2- (6- (difluoromethyl) pyridazin-4-yl) -1 H -indole-3-carbonitrile (134); 2- (6- (difluoromethyl) pyridazin-4-yl ) -1-methyl-1 H -indole-3-carbonitrile (135); 1-cyclopropyl-2- (6- (1-fluoroethyl) pyrazin-4-yl) -1 H- Benzo [ d ] imidazole-6-carbonitrile (136); and pharmaceutically acceptable salts thereof. A compound selected from the group consisting of: 1-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -5,6-difluoro-1 H -benzo [ d ] imidazole (42); 3-cyclopropyl-2- (6- (difluoromethyl) pyrazin-4-yl) -3 H -imidazo [4,5- b ] pyridine-5-methyl Nitrile (76); 1-cyclopropyl-2- (6- (trifluoromethyl) pyridazin-4-yl) -1 H -benzo [ d ] imidazole-6-carbonitrile (86); and Pharmaceutically acceptable salt.     A method for inhibiting metalloenzyme activity, comprising the step of contacting a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof with a metalloenzyme.         The method according to claim 56, wherein the aforementioned contact is in vivo.         The method according to claim 56, wherein the aforementioned contact is in vitro.         The method according to claim 58, wherein the metal enzyme comprises a metal atom, and the metal atom is iron, zinc, blood iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper.         The method according to claim 58, wherein the metalloenzyme is a member of an enzyme class selected from the group consisting of a cytochrome P450 family, a cyclooxygenase, and a nitric oxide synthase.         The method according to claim 58, wherein the metalloenzyme is aldosterone synthase (CYP11B2).         The method according to claim 58, wherein the metalloenzyme is an aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), a member of the nitric oxide synthase family, and coagulation lipids Synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-dissociating enzyme (CYP17), cytochrome P450 2A6 (CYP2A6), blood matrix oxygenase, indoleamine 2,3- Dioxidase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46 ), Cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).         The method according to claim 56, further comprising administering the aforementioned compound to a human subject.         A method for regulating metalloenzyme activity in a subject, comprising subjecting the aforementioned subject to the compound described in any one of claims 1 to 55 or a pharmacology thereof in an amount and under conditions sufficient to regulate the metalloenzyme activity. Steps for acceptable salt contact.         A method of treating a subject suffering from or susceptible to a condition or disease, wherein the aforementioned subject has been identified as in need of treatment of the aforementioned condition or disease, and the aforementioned method comprises administering to the subject in need thereof an effective amount of the subject as claimed The step of the compound or a pharmaceutically acceptable salt thereof according to any one of 1 to 55.         A method for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the aforementioned subject an effective amount of a compound according to any one of claims 1 to 55 or a pharmacologically thereof Acceptable salt steps.         A method for treating a subject suffering from or susceptible to a metalloenzyme related disorder or disease, wherein the aforementioned subject has been identified as in need of treatment for a metalloenzyme related disorder or disease, and the aforementioned method comprises administering to the aforementioned subject in need thereof an effective A step of measuring the compound according to any one of claims 1 to 55, so that the aforementioned subject can treat the aforementioned disorder or disease.         A method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the aforementioned subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, and the aforementioned method comprises administering to the aforementioned subject in need thereof A step with an effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54 so that the metalloenzyme activity of the aforementioned subject is adjusted.         The method according to any one of claims 65 to 68, wherein the aforementioned condition or disease is mediated by: aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylation Enzyme (CYP51), a member of the nitric oxide synthase family, prothrombin synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-dissociation enzyme (CYP17), cytochrome P450 2A6 (CYP2A6 ), Blood matrix oxygenase, indoleamine 2,3-dioxidase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cells Pigment P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).         The method according to any one of claims 65 to 69, wherein the aforementioned condition or disease is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central Nervous system (CNS) disease, urological disease, or gastrointestinal disease.         The method according to any one of claims 65 to 70, wherein the aforementioned condition or disease is hypertension, tolerant hypertension, a morbid state associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, and high pulmonary arteriality Blood pressure, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, renal disease, Post-myocardial infarction, coronary heart disease, fibrosis, diseases characterized by increased collagen formation, fibrosis accompanied by hypertension and matrix remodeling, fibrosis accompanied by abnormal endothelial cell function and matrix remodeling, cardiovascular disease , Renal dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular destruction, myocardial infarction, Left ventricular hypertrophy, vascular wall hypertrophy, thickened endothelium, fibrous necrosis such as arteries, kidney disease, diabetic Lesions, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic Fatty liver disease, kidney disease, diabetic kidney disease, or stroke.         A pharmaceutical composition comprising the compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.         The pharmaceutical composition according to claim 72, further comprising another therapeutic agent.         The pharmaceutical composition according to claim 73, wherein the additional therapeutic agent is an anticancer agent, antifungal agent, cardiovascular agent, anti-inflammatory agent, chemotherapeutic agent, antiangiogenic agent, cytotoxic agent, antiproliferative agent, metabolism Disease agent, ophthalmology disease agent, central nervous system (CNS) disease agent, urological disease agent, or gastrointestinal disease agent.         The method according to claim 65, wherein the subject is an animal different from a human.